Publications by authors named "Thomas Fischer"

518 Publications

Profiling and imaging of forensic evidence - A pan-European forensic round robin study part 1: Document forgery.

Sci Justice 2022 Jul 7;62(4):433-447. Epub 2022 Jun 7.

Department of Experimental Physics, Rudjer Boskovic Institute, Bijenicka c. 54, 10000 Zagreb, Croatia.

The forensic scenario, on which the round robin study was based, simulated a suspected intentional manipulation of a real estate rental agreement consisting of a total of three pages. The aims of this study were to (i) establish the amount and reliability of information extractable from a single type of evidence and to (ii) provide suggestions on the most suitable combination of compatible techniques for a multi-modal imaging approach to forgery detection. To address these aims, seventeen laboratories from sixteen countries were invited to answer the following tasks questions: (i) which printing technique was used? (ii) were the three pages printed with the same printer? (iii) were the three pages made from the same paper? (iv) were the three pages originally stapled? (v) were the headings and signatures written with the same ink? and (vi) were headings and signatures of the same age on all pages? The methods used were classified into the following categories: Optical spectroscopy, including multispectral imaging, smartphone mapping, UV-luminescence and LIBS; Infrared spectroscopy, including Raman and FTIR (micro-)spectroscopy; X-ray spectroscopy, including SEM-EDX, PIXE and XPS; Mass spectrometry, including ICPMS, SIMS, MALDI and LDIMS; Electrostatic imaging, as well as non-imaging methods, such as non-multimodal visual inspection, (micro-)spectroscopy, physical testing and thin layer chromatography. The performance of the techniques was evaluated as the proportion of discriminated sample pairs to all possible sample pairs. For the undiscriminated sample pairs, a distinction was made between undecidability and false positive claims. It was found that none of the methods used were able to solve all tasks completely and/or correctly and that certain methods were a priori judged unsuitable by the laboratories for some tasks. Correct results were generally achieved for the discrimination of printer toners, whereas incorrect results in the discrimination of inks. For the discrimination of paper, solid state analytical methods proved to be superior to mass spectrometric methods. None of the participating laboratories deemed addressing ink age feasible. It was concluded that correct forensic statements can only be achieved by the complementary application of different methods and that the classical approach of round robin studies to send standardised subsamples to the participants is not feasible for a true multimodal approach if the techniques are not available at one location.
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http://dx.doi.org/10.1016/j.scijus.2022.06.001DOI Listing
July 2022

Stiffness of Muscles and Tendons of the Lower Limb of Professional and Semiprofessional Athletes Using Shear Wave Elastography.

J Ultrasound Med 2022 Jul 28. Epub 2022 Jul 28.

Department of Radiology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Objective: Shear wave elastography (SWE) allows assessment of muscle and tendon stiffness and can be used to diagnose soft tissue pathologies such as tendinopathies. In sports medicine, SWE may have the potential to uncover structural changes early on before they lead to functional impairment. To systematically analyze possible differences in tendon and muscle stiffness of the lower limb between professional (PG) and semiprofessional female athletes (SG) using SWE and to compile reference values for developing preventive medicine approaches for professional athletes.

Methods: Standardized SWE of both lower limb tendons and muscles (Achilles tendon [AT], soleus muscle insertion [SM], patellar tendon [PT], quadriceps tendon [QT], vastus medialis muscle [VM]) in the longitudinal plane was performed with the tendons in relaxed position in 24 healthy professional female athletes (PG) in comparison with 24 healthy semiprofessional female athletes (SG).

Results: Median tendon and muscle stiffness was significantly higher in professional athletes (AT:PG, 11.12 m/s vs SG, 7.33 m/s, P < .001; SM: 1.77 m/s vs 1.14 m/s, P < .001; VM: 1.63 m/s vs 0.87 m/s, P < .001; QT: 3.31 m/s vs 2.61 m/s, P < .05). There was no significant difference in patellar tendon stiffness between PG and SG (PT: 2.57 m/s vs 3.21, P = .25).

Conclusion: Professional female athletes have higher stiffness values than semiprofessional female athletes in lower limb muscles and tendons, except for the patellar tendon. Knowledge of such differences is necessary for diagnosing tendinopathy and injuries. Musculoskeletal SWE could offer great benefits in sports medicine as well as in rehabilitation and preventive medicine.
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http://dx.doi.org/10.1002/jum.16062DOI Listing
July 2022

Dorsal Root Ganglia Volume-Normative Values, Correlation with Demographic Determinants and Reliability of Three Different Methods of Volumetry.

Diagnostics (Basel) 2022 Jun 28;12(7). Epub 2022 Jun 28.

Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.

Dorsal root ganglia (DRG) volume assessment by MR-Neurography (MRN) has evolved to an important imaging marker in the diagnostic workup of various peripheral neuropathies and pain syndromes. The aim of this study was (1) to assess normal values of DRG volume and correlations with demographic determinants and (2) to quantify the inter-reader and inter-method reliability of three different methods of DRG volumetry. Sixty healthy subjects (mean age: 59.1, range 23-79) were examined using a 3D T2-weighted MRN of the lumbosacral plexus at 3 Tesla. Normal values of DRG L3 to S2 were obtained after exact volumetry based on manual 3D segmentation and correlations with demographic variables were assessed. For the assessment of inter-reader and inter-method reliability, DRG volumes in a subset of 25 participants were measured by two independent readers, each applying (1) exact volumetry based on 3D segmentation, (2) axis-corrected, and (3) non-axis-corrected volume estimation. Intraclass correlation coefficients were reported and the Bland-Altman analysis was conducted. Mean DRG volumes ranged from 124.8 mm for L3 to 323.3 mm for S1 and did not differ between right and left DRG. DRG volume (mean of L3 to S1) correlated with body height (r = 0.42; = 0.0008) and weight (r = 0.34; = 0.0087). DRG of men were larger than of women ( = 0.0002); however, no difference remained after correction for body height. Inter-reader reliability was high for all three methods but best for exact volumetry (ICC = 0.99). While axis-corrected estimation was not associated with a relevant bias, non-axis-corrected estimation systematically overestimated DRG volume by on average of 15.55 mm (reader 1) or 18.00 mm (reader 2) when compared with exact volumetry. The here presented normal values of lumbosacral DRG volume and the correlations with height and weight may be considered in future disease specific studies and possible clinical applications. Exact volumetry was most reliable and should be considered the gold standard. However, the reliability of axis-corrected and non-axis-corrected volume estimation was also high and might still be sufficient, depending on the degree of the required measurement accuracy.
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http://dx.doi.org/10.3390/diagnostics12071570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323629PMC
June 2022

Concepts in the Establishment of Interdisciplinary Ultrasound Centers: The Role of Radiology.

Rofo 2022 Jul 18. Epub 2022 Jul 18.

Department of Radiology, ChariteCentrum 6 Diagnostische und interventionelle Radiologie und Nuklearmedizin, Berlin, Germany.

Background:  Ultrasound (US) is widely used as a fast and cost-efficient first-choice imaging technique without relevant side effects for a variety of diagnostic tasks. Due to technical advances, more complex and sophisticated methods such as color-coded duplex ultrasound, image fusion, contrast-enhanced ultrasound (CEUS), and ultrasound-guided interventions have become increasingly important in diagnostic algorithms.

Method:  This study presents an overview of all aspects regarding the establishing of an interdisciplinary US center based on five representative examples in Germany. These aspects include topics of ultrasound education, research, economics, and administration.

Results:  The goal of an interdisciplinary US center is to bundle the use of equipment, staff, rooms, and infrastructure resources (optimization of equipment availability and use of new techniques) to expand the range of examinations, to promote resident training, and to boost continuing medical education of residents. This should result in better patient care and has additionally improved patient care while considering the added value for the participating institutions involved. Interdisciplinary US centers allow a reduction of the number of US devices needed in a hospital and more efficient use of available equipment through bedside time optimization by central organization within interdisciplinary management. The focused application of special US techniques such as CEUS or image fusion for complex, difficult interventions as well as the training and education of younger colleagues in using these techniques is centrally organized by experts and can be improved through the multidisciplinary experience available.

Conclusion:  Organizational structures, sharing of materials, and standardization of diagnostic reports facilitate and accelerate cooperation with the referring specialty.

Key Points:   · Interdisciplinary US centers foster clinical collaboration, research, and jointly organized, standardized training.. · Economic aspects include optimization of available equipment, use of the latest US techniques, and centralization of organizational structures.. · Common terminology and standardized reporting increase the satisfaction of referring doctors.

Citation Format: · Clevert DA, Jung EM, Weber M et al. Concepts in the Establishment of Interdisciplinary Ultrasound Centers: The Role of Radiology. Fortschr Röntgenstr 2022; DOI: 10.1055/a-1853-7443.
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http://dx.doi.org/10.1055/a-1853-7443DOI Listing
July 2022

Atrioventricular 2:1-conduction via an accessory pathway during left atrial flutter unmasking WPW syndrome: a case report.

Eur Heart J Case Rep 2022 Jul 28;6(7):ytac250. Epub 2022 Jun 28.

Department of Internal Medicine I, University of Wuerzburg, University Clinic, Oberdürrbacherstraße 6, D-97080 Wuerzburg, Germany.

Background: Implantable cardioverter defibrillators (ICDs) are most effective in treating sudden cardiac death. However, accurate diagnostic workup of broad complex tachycardia is crucial to ensure correct indication for ICD treatment and to avoid unnecessary invasive treatment and device-associated morbidity.

Case Summary: We present a case of atypical atrial flutter with 2:1 atrioventricular (AV) conduction via a left-posterior accessory pathway (AP), leading to the diagnosis of Wolff-Parkinson-White (WPW) syndrome. Upon admission, the 72-year-old patient showed a regular broad complex tachycardia with superior axis and positive concordance in precordial leads, suggestive of either ventricular tachycardia (VT), antidromic AV re-entrant tachycardia (AVRT), or supraventricular tachycardia with antegrade conduction via a left-posterior AP. Interrogation of the two-chamber ICD, which was very likely implanted unjustified in a peripheral clinic before, revealed atrial flutter with 2:1 AV conduction. Remarkably, after the restoration of sinus rhythm, no classic echocardiogram (ECG) criteria for preexcitation syndrome were detected. An invasive electrophysiological study proved the diagnosis of a bidirectionally conducting, left-posterior AP, which was successfully ablated.

Discussion: Differential diagnosis of broad complex tachycardia with superior axis and positive concordance of chest leads consists of i) VT with a left ventricular exit at the posterior mitral annulus, ii) antidromic AVRT involving a left-posterior AP, and iii) supraventricular tachycardia predominantly conducted via a left-posterior AP. The absence of classic ECG criteria for preexcitation syndrome does not rule out AP sufficiently, highlighting the importance of minimal surface-ECG preexcitation criteria. In the case of detection of minimal surface-ECG preexcitation criteria, administration of adenosine rules out or proves the existence of an AP noninvasively and cost-effectively.
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http://dx.doi.org/10.1093/ehjcr/ytac250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272436PMC
July 2022

[Catheter ablation for atrial fibrillation - standard of care and future perspectives].

Dtsch Med Wochenschr 2022 Jul 4;147(13):858-873. Epub 2022 Jul 4.

Atrial fibrillation is the most frequent cardiac arrhythmia in adults. For symptomatic atrial fibrillation, catheter ablation has proven to be an effective and safe treatment that is superior to antiarrhythmic drug treatment regarding quality of life and maintenance of normal sinus rhythm. Moreover, there is increasing evidence that early rhythm control and catheter ablation can be of prognostic benefit. Especially heart failure patients with impaired left ventricular systolic function seem to benefit from rhythm control therapy by catheter ablation. Furthermore, technological innovations such as novel single-shot devices, contact force mapping, the concept of high-power-short-duration (HPSD) ablation and implementation of electroporation (pulsed field ablation) offer the prospect of further improving ablation efficiency and safety. This review provides an overview of current standards of care as well as future trends in atrial fibrillation catheter ablation techniques.
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http://dx.doi.org/10.1055/a-1477-4020DOI Listing
July 2022

Head-to-Head Comparison of [ Ga]Ga-FAPI-46-PET/CT and [F]F-FDG-PET/CT for Radiotherapy Planning in Head and Neck Cancer.

Mol Imaging Biol 2022 Jun 30. Epub 2022 Jun 30.

Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Introduction: In head and neck cancers (HNCs), fibroblast activation protein (FAP) is expressed by cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Preliminary evidence suggests that detection and staging is feasible with positron emission tomography (PET/CT) imaging using [ Ga]-radiolabeled inhibitors of FAP ([ Ga]Ga-FAPI-46) in HNCs. This study aims to compare [ Ga]Ga-FAPI-46 PET/CT and [F]-fluorodeoxy-D-glucose ([F]F-FDG) PET/CT with a focus on improved target volume definition and radiotherapy planning in patients with HNC referred for chemoradiation.

Methods: A total of 15 patients with HNCs received both [ Ga]Ga-FAPI-46 PET/CT and [F]F-FDG PET/CT with a thermoplastic mask, in addition to initial tumor staging by conventional imaging with contrast-enhanced CT and/or MRI. Mean intervals between FAPI/FDG and FAPI/conventional imaging were 4 ± 20 and 17 ± 18 days, respectively. Location and number of suspicious lesions revealed by the different procedures were recorded. Subsequently, expert-generated gross tumor volumes (GTVs) based on conventional imaging were compared to those based on [F]F-FDG and [ Ga]Ga-FAPI-46 PET/CT to measure the impact on subsequent radiation planning.

Results: All patients had focal FAPI uptake above background in tumor lesions. Compared to FDG, tumor uptake (median SUVmax 10.2 vs. 7.3, p = 0.008) and tumor-to-background ratios were significantly higher with FAPI than with FDG (SUVmean liver: 9.3 vs. 3.2, p < 0.001; SUVmean bloodpool: 6.9 vs. 4.0, p < 0.001). A total of 49 lesions were recorded. Of these, 40 (82%) were FDG and 41 (84%) were FAP. There were 5 (10%) FAP/FDG lesions and 4 (8%) FAP/FDG lesions. Volumetrically, a significant difference was found between the GTVs (median 57.9 ml in the FAPI-GTV, 42.5 ml in the FDG-GTV, compared to 39.2 ml in the conventional-GTV). Disease stage identified by FAPI PET/CT was mostly concordant with FDG PET/CT. Compared to conventional imaging, five patients (33%) were upstaged following imaging with FAPI and FDG PET/CT.

Conclusion: We demonstrate that [ Ga]Ga-FAPI-46 -PET/CT is useful for detecting tumor lesions in patients with HNCs. There is now a need for prospective randomized studies to confirm the role of [ Ga]Ga-FAPI-46 PET/CT in relation to [F]F-FDG PET/CT in HNCs and to evaluate its impact on clinical outcome.
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http://dx.doi.org/10.1007/s11307-022-01749-7DOI Listing
June 2022

Semiquantitative 3T Brain Magnetic Resonance Imaging for Dynamic Visualization of the Glymphatic-Lymphatic Fluid Transport System in Humans: A Pilot Study.

Invest Radiol 2022 Aug 1;57(8):544-551. Epub 2022 Apr 1.

Institute of Neuroradiology, University Hospital of LMU Munich.

Objectives: Recently, a novel clearing system for interstitial solutes of the brain was described as a perivascular pathway named the glymphatic system. Furthermore, lymphatic vessels were found in the meninges to drain interstitial fluids. It is hypothesized that interstitial solutes, such as amyloid β, are firstly processed through the brain by the glymphatic system and secondly drained out of the brain by lymphatic vessels (glymphatic-lymphatic fluid transport system [GLS]). Since then, various neurological disorders, such as Alzheimer disease, have been associated with a dysfunction of the GLS. In the current study, we aimed to establish a clinical magnetic resonance imaging (MRI) study protocol for visualizing lymphatic vessels as part of the GLS in humans. More importantly, we aimed to describe the dynamic changes of a contrast agent in these lymphatic vessels over time.

Materials And Methods: Twenty volunteers with an unremarkable neurological/psychiatric history were included in this 3T MRI study. Serial MRI sequence blocks were performed at 3 predefined time points (TPs): TP 1, precontrast MRI before administration of a gadolinium-based contrast agent (GBCA); TP 2, immediately post-GBCA (early ce-MRI); and TP 3, 60 minutes post-GBCA (late ce-MRI). Each MRI block contained the following sequences obtained in the same order: whole-brain 3D T1-MPRAGE, whole-brain 3D T2-FLAIR, focused 2D T2-FLAIR, and whole-brain 3D T1-SPACE. Signal intensity (SI) in compartments of the GLS adjacent to the superior sagittal sinus, gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) was calculated by manually placed regions of interest. The time course of the signal intensities was examined by generalized linear mixed models. The data were adjusted for age, cognitive function (Montreal-Cognitive-Assessment test), and sleep quality (Pittsburgh Sleep Quality Index questionnaire).

Results: The GLS was best visualized in the 2D T2-FLAIR and 3D T1-SPACE sequences, enabling further SI measurement. In precontrast (TP 1), the SI within the GLS was significantly higher than in CSF and significantly lower than in GM and WM. In post-GBCA, a significant increase (TP 2) and decrease (TP 3), respectively, of the GLS SI values were noted (86.3 ± 25.2% increase and subsequent decrease by 25.4 ± 9% in the 3D T1-SPACE sequence). The SI values of CSF, GM, and WM did not change significantly between the 3 TPs.

Conclusions: A clinical MRI study protocol was established for the visualization of lymphatic vessels as an important part of the GLS and therefore the brain's clearing mechanism of interstitial solutes. Furthermore, dynamic changes in the GLS were described over time, possibly reflecting the clearing function of the GLS. This might constitute the basis for evaluating the GLS function in manifold neurological pathologies in the future.
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http://dx.doi.org/10.1097/RLI.0000000000000870DOI Listing
August 2022

The Shape of Human Red Blood Cells Suspended in Autologous Plasma and Serum.

Authors:
Thomas M Fischer

Cells 2022 06 16;11(12). Epub 2022 Jun 16.

Department of Experimental Physics, Saarland University, Campus E2 6, 66123 Saarbrücken, Germany.

(1) Background: In almost all studies of the shape of the human red blood cell (RBC), the suspending medium was a salt solution supplemented with albumin. However, the ratio of thickness across the dimple region to the thickness of the rim (THR) depends on the albumin concentration. Values of the THR in the literature range from 0.27 to 0.627 whereas in the present work it was 0.550 or 0.601 whether measured in plasma or serum. (2) Methods: 9911 RBCs of eight donors were suspended in autologous plasma or serum. Sedimented RBCs were observed under bright field illumination at 416 nm. From the profiles of gray value, the THR was determined. (3) Results: The THR displays a wide distribution within a single blood sample. A direct correlation of THR and spontaneous curvature of the membrane is likely. The variation of the mean THR between different donors is large. The aspect ratio of RBCs viewed face-on ranged on average from 1 to 1.48. In oval RBCs, the rim is thicker along the major axis than along the minor axis, an effect increasing with increasing aspect ratio. Remodeling of the membrane skeleton occurs in vivo with a characteristic time (τ) on the order of 1 h. (4) Conclusions: Consideration of these data in models of RBC behavior might improve the agreement with observations. τ≈1 h suggests a more general type of reference configuration of the membrane skeleton than a stress free shape.
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http://dx.doi.org/10.3390/cells11121941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9222013PMC
June 2022

Thermally-induced drift of A-site cations at solid-solid interface in physically paired lead halide perovskites.

Sci Rep 2022 Jun 17;12(1):10241. Epub 2022 Jun 17.

Chemistry Department, Institute of Inorganic Chemistry, University of Cologne, Greinstr. 6, 50939, Cologne, Germany.

The promise of hybrid organic-inorganic halide perovskite solar cells rests on their exceptional power conversion efficiency routinely exceeding 25% in laboratory scale devices. While the migration of halide ions in perovskite thin films has been extensively investigated, the understanding of cation diffusion remains elusive. In this study, a thermal migration of A‑site cations at the solid-solid interface, formed by two physically paired MAPbI and FAPbI perovskite thin films casted on FTO, is demonstrated through continuous annealing at comparably low temperature (100 °C). Diffusion of methylammonium (CHNH, MA) cations into the low‑symmetry yellow δ‑FAPbI phase triggers a transition from the yellow (δ) to black (α) phase evident in the distinctive color change and verified by shifts in absorption bands and X‑ray diffraction patterns. Intermixing of the A‑site cations MA and FA (CH(NH)) occurred for both systems, α‑MAPbI/δ‑FAPbI and α‑MAPbI/α‑FAPbI. The structural and compositional changes in both cases support a thermally activated ion drift unambiguously demonstrated through changes in the absorption and X-ray photoelectron spectra. Moreover, the physical contact annealing (PCA) leads to healing of defects and pinholes in α‑MAPbI thin films, which was correlated to longer recombination lifetimes in mixed MAFAPbI thin films obtained after PCA and probed by ultrafast transient absorption spectroscopy.
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http://dx.doi.org/10.1038/s41598-022-14452-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205985PMC
June 2022

Diagnostic value of contrast-enhanced ultrasound (CEUS) in kidney allografts - 12 years of experience in a tertiary referral center.

Clin Hemorheol Microcirc 2022 Jun 2. Epub 2022 Jun 2.

Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Memberof Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: B-Mode and Doppler ultrasound are standard diagnostic techniques for early postoperative monitoring and long-term follow-up of kidney transplants. In certain cases, contrast-enhanced ultrasound (CEUS) is used to clarify unclear Doppler findings.

Objective: To investigate the diagnostic performance of CEUS in the workup of renal allograft pathologies.

Methods: A systematic search for CEUS examinations of renal transplants conducted in our department between 2008 and 2020 was performed using the following inclusion criteria: i) patient age ≥18 years and ii) confirmation of diagnosis by biopsy and histopathology, imaging follow-up by CEUS, contrast-enhanced computed tomography (ceCT), contrast-enhanced magnetic resonance imaging (ceMRI), or angiography, or intraoperative findings. Exclusion criteria were: i) CEUS performed in the setting of a study and ii) CEUS for other indications than dedicated renal transplant examination. Statistical analysis was performed separately for subgroups with different indications (focal vs non-focal).

Results: Overall, 78 patients were included in the statistical analysis, which revealed high sensitivity (92.2%, 95% -confidence interval [CI] 81.5-96.9%) and high specificity (88.9%, 95% -CI 71.9-96.1%) of CEUS.

Conclusions: The high diagnostic performance demonstrated here and the superficial location of kidney allografts advocate the additional use of CEUS in the follow-up of renal transplant recipients.
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http://dx.doi.org/10.3233/CH-211357DOI Listing
June 2022

PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy.

Cell Biosci 2022 Apr 27;12(1):50. Epub 2022 Apr 27.

Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany.

Background: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy.

Results: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model.

Conclusion: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
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http://dx.doi.org/10.1186/s13578-022-00778-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044846PMC
April 2022

Diagnostic Yield of Genetic Testing in Young Patients With Atrioventricular Block of Unknown Cause.

J Am Heart Assoc 2022 05 26;11(9):e025643. Epub 2022 Apr 26.

Department of Cardiology Aarhus University Hospital Aarhus Denmark.

Background The cause of atrioventricular block (AVB) remains unknown in approximately half of young patients with the diagnosis. Although variants in several genes associated with cardiac conduction diseases have been identified, the contribution of genetic variants in younger patients with AVB is unknown. Methods and Results Using the Danish Pacemaker and Implantable Cardioverter Defibrillator (ICD) Registry, we identified all patients younger than 50 years receiving a pacemaker because of AVB in Denmark in the period from January 1, 1996 to December 31, 2015. From medical records, we identified patients with unknown cause of AVB at time of pacemaker implantation. These patients were invited to a genetic screening using a panel of 102 genes associated with inherited cardiac diseases. We identified 471 living patients with AVB of unknown cause, of whom 226 (48%) accepted participation. Median age at the time of pacemaker implantation was 39 years (interquartile range, 32-45 years), and 123 (54%) were men. We found pathogenic or likely pathogenic variants in genes associated with or possibly associated with AVB in 12 patients (5%). Most variants were found in the gene (n=5). variant carriers all had a family history of either AVB and/or sudden cardiac death. Conclusions In young patients with AVB of unknown cause, we found a possible genetic cause in 1 out of 20 participating patients. Variants in the gene were most common and associated with a family history of AVB and/or sudden cardiac death, suggesting that genetic testing should be a part of the diagnostic workup in these patients to stratify risk and screen family members.
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http://dx.doi.org/10.1161/JAHA.121.025643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9238593PMC
May 2022

Genetic Knock-out of TNFR1 and TNFR2 in a JAK2-V617F Polycythemia Vera Mouse Model.

Hemasphere 2022 May 15;6(5):e717. Epub 2022 Apr 15.

Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Center, Otto-von-Guericke University, Magdeburg, Germany.

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http://dx.doi.org/10.1097/HS9.0000000000000717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015207PMC
May 2022

Dual-tracer PET/CT protocol with [F]-FDG and [Ga]Ga-FAPI-46 for cancer imaging - a proof of concept.

J Nucl Med 2022 Apr 14. Epub 2022 Apr 14.

University Hospital of Cologne, Germany.

Imaging studies with PET tracers acting as fibroblast activation protein inhibitors (FAPI) show promising results that could usefully complement [F]-FDG in cancer imaging. All patients received [F]-FDG-PET/CT and dual-tracer PET/CT after additional injection of [Ga]Ga-FAPI-46 following the [F]-FDG-PET/CT. Two readers visually compared detection rate and analyzed target-to-background uptake ratios (TBRs) for tumor and metastatic tissue in single and dual-tracer PET/CT. Detection rate in dual-tracer PET/CT was visually as good as that in single-tracer PET/CT in four patients and superior in two patients, whereas TBRs were significantly higher in dual-tracer PET/CTs. We demonstrate the feasibility and potential of dual-tracer [F]-FDG-[Ga]Ga-FAPI-46-PET/CT administered within a single session. The dual-tracer approach may have superior sensitivity to [F]-FDG-PET/CT alone without compromising individual assessment of either scan.
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http://dx.doi.org/10.2967/jnumed.122.263835DOI Listing
April 2022

Quantitative Multiparametric Ultrasound (mpUS) in the Assessment of Inconclusive Cervical Lymph Nodes.

Cancers (Basel) 2022 Mar 22;14(7). Epub 2022 Mar 22.

Department of Radiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Charitéplatz 1, 10117 Berlin, Germany.

Background: Enlarged cervical lymph nodes (CLN) are preferably examined by ultrasound (US) by using criteria such as size and echogenicity to assess benign and suspicious CLN, which should be histologically evaluated. This study aims to assess the differentiation of malign and benign CLN by using multiparametric US applications (mpUS).

Methods: 101 patients received a standardized US protocol prior to surgical intervention using B-mode-US, shear-wave elastography (SWE) and contrast-enhanced ultrasound (CEUS). SWE was assessed by 2D real-time SWE conducting a minimum of five measurements, CEUS parameters were assessed with post-processing perfusion software. Histopathological confirmation served as the gold standard.

Results: B-mode-US and SWE analysis of 104 CLN (36 benign, 68 malignant) showed a significant difference between benign and malignant lesions, presenting a larger long axis and higher tissue stiffness (both < 0.001). Moreover, tissue stiffness assessed by SWE was significantly higher in CLN with regular B-mode-US criteria (Solbiati Index > 2 and short-axis < 1 cm, < 0.001). No perfusion parameter on CEUS showed a significant differentiation between benign and malignant CLN.

Discussion: As the only multiparametric parameter, SWE showed higher tissue stiffness in malignant CLN, also in subgroups with regular B-mode criteria. This fast and easy application may be a promising noninvasive tool to US examination to ameliorate the sonographic differentiation of inconclusive CLN.
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http://dx.doi.org/10.3390/cancers14071597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997164PMC
March 2022

Randomized Trial of a Supportive Psychotherapy for Parents of Adolescents and Young Adults With Hematologic Malignancies.

J Natl Compr Canc Netw 2022 Apr 11:1-15. Epub 2022 Apr 11.

1Department of Hematology and Oncology, University Hospital Magdeburg.

Background: Cancer regularly disrupts health and developmental trajectories in adolescents and young adults (AYAs). Parents have been shown to have a substantial impact on the health and cancer survivorship activities of AYA patients in the form of symptom management. However, no randomized controlled trial has evaluated a coping support intervention (CSI) program for parents of AYAs with cancer aged 18 to 40 years.

Patients And Methods: From November 30, 2012, to August 29, 2016, parents of AYAs with hematologic malignancies were randomized in a phase III controlled trial (1:1 ratio, stratified sampling) to either the research-based CSI AYA-Parents group (CSI group; n=82) or the standard care (SC) group (n=70). CSI consisted of 5 sessions to achieve the enhancement of parental adaptive coping as the primary outcome (per the adaptive coping scale of the 28-item Brief COPE, a validated multidimensional self-assessment-questionnaire recommended for clinical cancer research). Measures of adaptive coping, depression, and mental health were collected at pre-CSI (measurement date T1), at the end of the intervention sessions (measurement date T2), and at follow-up (3 months). We calculated mean change scores in outcomes and estimated intervention effect sizes (Cohen's d) for changes from T1 to T2/T3, with 0.2 indicating a small effect, 0.5 a medium effect, and 0.8 a large effect. All statistical tests were 2-sided.

Results: In the intention-to-treat analysis, the CSI group significantly improved their adaptive coping compared with the SC group (95% CI, 0.30-2.54; P=.013; d=0.405), whereas adaptive coping in the SC group deteriorated. The CSI group also experienced a significant decrease in depressive symptoms and improved mental health with clinical significance (95% CI, -1.98 to -0.30; P=.008; d=0.433, and 95% CI, -0.19 to 3.97; P=.074; d=0.292, respectively). Sensitivity analyses confirmed the robustness of the main intention-to-treat analysis.

Conclusions: CSI improved effectively adaptive coping and depression in parents of AYAs with hematologic malignancies. It may represent a novel family-based approach in AYA oncology care.
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http://dx.doi.org/10.6004/jnccn.2021.7075DOI Listing
April 2022

Diagnostic performance of MRI and US in suspicion of penile fracture.

Transl Androl Urol 2022 Mar;11(3):377-385

Department of Radiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Background: Penile fracture (PF) is defined as rupture of the tunica albuginea of the corpora cavernosa. While most authors agree that rapid surgical therapy of this rare pathology leads to the best patient outcome, the role of imaging is highly controversial in the published literature. To obtain further evidence concerning the diagnostic accuracies of magnetic resonance imaging (MRI) and ultrasound (US) in the diagnostic assessment of patients with suspected PF.

Methods: We systematically reviewed MRI and US examinations performed in our institution between 2000 and 2021 and correlated imaging reports with either intraoperative finding or final clinical diagnosis. Inclusion criteria were: (I) patient age ≥18 years, (II) examination between 2000 and 2021, (III) information available on patient's history and clinical presentation, and (IV) documented final diagnosis in discharge letter. Next to diagnostic accuracy, we describe typical imaging findings such as penile hematoma, tear of the tunica albuginea including location in terms of side and shaft segment affected, and involvement of corpus spongiosum.

Results: Overall, 46 of 88 included patients (54.5%) had a confirmed diagnosis of PF. A total of 69 MRI and 31 US examinations were included. Sensitivity and specificity were 91.9% (95% CI: 78.7-97.2%) and 90.6% (95% CI: 75.8-96.8%) for MRI and 71.4% (95% CI: 45.4-88.3%) and 100.0% (95% CI: 81.6-100.0%) for US, respectively.

Conclusions: The results of the present study suggest that MRI is more suitable to confirm PF and identify the site of the associated tunica albuginea tear while US is a good tool for ruling out PF.
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http://dx.doi.org/10.21037/tau-21-957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8984979PMC
March 2022

Assessment of Artificial Intelligence in Echocardiography Diagnostics in Differentiating Takotsubo Syndrome From Myocardial Infarction.

JAMA Cardiol 2022 05;7(5):494-503

Heart Department, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy.

Importance: Machine learning algorithms enable the automatic classification of cardiovascular diseases based on raw cardiac ultrasound imaging data. However, the utility of machine learning in distinguishing between takotsubo syndrome (TTS) and acute myocardial infarction (AMI) has not been studied.

Objectives: To assess the utility of machine learning systems for automatic discrimination of TTS and AMI.

Design, Settings, And Participants: This cohort study included clinical data and transthoracic echocardiogram results of patients with AMI from the Zurich Acute Coronary Syndrome Registry and patients with TTS obtained from 7 cardiovascular centers in the International Takotsubo Registry. Data from the validation cohort were obtained from April 2011 to February 2017. Data from the training cohort were obtained from March 2017 to May 2019. Data were analyzed from September 2019 to June 2021.

Exposure: Transthoracic echocardiograms of 224 patients with TTS and 224 patients with AMI were analyzed.

Main Outcomes And Measures: Area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity of the machine learning system evaluated on an independent data set and 4 practicing cardiologists for comparison. Echocardiography videos of 228 patients were used in the development and training of a deep learning model. The performance of the automated echocardiogram video analysis method was evaluated on an independent data set consisting of 220 patients. Data were matched according to age, sex, and ST-segment elevation/non-ST-segment elevation (1 patient with AMI for each patient with TTS). Predictions were compared with echocardiographic-based interpretations from 4 practicing cardiologists in terms of sensitivity, specificity, and AUC calculated from confidence scores concerning their binary diagnosis.

Results: In this cohort study, apical 2-chamber and 4-chamber echocardiographic views of 110 patients with TTS (mean [SD] age, 68.4 [12.1] years; 103 [90.4%] were female) and 110 patients with AMI (mean [SD] age, 69.1 [12.2] years; 103 [90.4%] were female) from an independent data set were evaluated. This approach achieved a mean (SD) AUC of 0.79 (0.01) with an overall accuracy of 74.8 (0.7%). In comparison, cardiologists achieved a mean (SD) AUC of 0.71 (0.03) and accuracy of 64.4 (3.5%) on the same data set. In a subanalysis based on 61 patients with apical TTS and 56 patients with AMI due to occlusion of the left anterior descending coronary artery, the model achieved a mean (SD) AUC score of 0.84 (0.01) and an accuracy of 78.6 (1.6%), outperforming the 4 practicing cardiologists (mean [SD] AUC, 0.72 [0.02]) and accuracy of 66.9 (2.8%).

Conclusions And Relevance: In this cohort study, a real-time system for fully automated interpretation of echocardiogram videos was established and trained to differentiate TTS from AMI. While this system was more accurate than cardiologists in echocardiography-based disease classification, further studies are warranted for clinical application.
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http://dx.doi.org/10.1001/jamacardio.2022.0183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968683PMC
May 2022

Thromboinflammation in Myeloproliferative Neoplasms (MPN)-A Puzzle Still to Be Solved.

Int J Mol Sci 2022 Mar 16;23(6). Epub 2022 Mar 16.

Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.

Myeloproliferative neoplasms (MPNs), a group of malignant hematological disorders, occur as a consequence of somatic mutations in the hematopoietic stem cell compartment and show excessive accumulation of mature myeloid cells in the blood. A major cause of morbidity and mortality in these patients is the marked prothrombotic state leading to venous and arterial thrombosis, including myocardial infarction (MI), deep vein thrombosis (DVT), and strokes. Additionally, many MPN patients suffer from inflammation-mediated constitutional symptoms, such as fever, night sweats, fatigue, and cachexia. The chronic inflammatory syndrome in MPNs is associated with the up-regulation of various inflammatory cytokines in patients and is involved in the formation of the so-called MPN thromboinflammation. JAK2-V617F, the most prevalent mutation in MPNs, has been shown to activate a number of integrins on mature myeloid cells, including granulocytes and erythrocytes, which increase adhesion and drive venous thrombosis in murine knock-in/out models. This review aims to shed light on the current understanding of thromboinflammation, involvement of neutrophils in the prothrombotic state, plausible molecular mechanisms triggering the process of thrombosis, and potential novel therapeutic targets for developing effective strategies to reduce the MPN disease burden.
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http://dx.doi.org/10.3390/ijms23063206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954909PMC
March 2022

Functional Aplasia of the Contralateral A1 Segment Influences Clinical Outcome in Patients with Occlusion of the Distal Internal Carotid Artery.

J Clin Med 2022 Feb 26;11(5). Epub 2022 Feb 26.

Institute of Diagnostic and Interventional Radiology, Neuroradiology and Nuclear Medicine, Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, 44892 Bochum, Germany.

Background: The importance of an A1 aplasia remains unclear in stroke patients. In this work, we analyze the impact of an A1 aplasia contralateral to an acute occlusion of the distal internal carotid artery (ICA) on clinical outcomes.

Methods: We conducted a retrospective study of consecutive stroke patients treated with mechanical thrombectomy at 12 tertiary care centers between January 2015 and February 2021 due to an occlusion of the distal ICA. Functional A1 aplasia was defined as the absence of A1 or hypoplastic A1 (>50% reduction to the contralateral site). Functional independence was measured by the modified Rankin Scale (mRS ≤ 2).

Results: In total, 81 out of 1068 (8%) patients had functional A1 aplasia contralateral to distal ICA occlusion. Patients with functional contralateral A1 aplasia were more severely affected on admission (median NIHSS 18, IQR 15-23 vs. 17, IQR 13-21; aOR: 0.672, 95% CI: 0.448-1.007, = 0.054) and post-interventional ischemic damage was larger (median ASPECTS 5, IQR 1-7, vs. 6, IQR 3-8; aOR: 1.817, 95% CI: 1.184-2.789, = 0.006). Infarction occurred more often within the ipsilateral ACA territory (20/76, 26% vs. 110/961, 11%; aOR: 2.482, 95% CI: 1.389-4.437, = 0.002) and both ACA territories (8/76, 11% vs. 5/961, 1%; aOR: 17.968, 95% CI: 4.979-64.847, ≤ 0.001). Functional contralateral A1 aplasia was associated with a lower rate of functional independence at discharge (6/81, 8% vs. 194/965, 20%; aOR: 2.579, 95% CI: 1.086-6.122, = 0.032) and after 90 days (5/55, 9% vs. 170/723, 24%; aOR: 2.664, 95% CI: 1.031-6.883, = 0.043).

Conclusions: A functional A1 aplasia contralateral to a distal ICA occlusion is associated with a poorer clinical outcome.
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http://dx.doi.org/10.3390/jcm11051293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911253PMC
February 2022

Liquid-Liver Phantom: Mimicking the Viscoelastic Dispersion of Human Liver for Ultrasound- and MRI-Based Elastography.

Invest Radiol 2022 Aug 23;57(8):502-509. Epub 2022 Feb 23.

From the Department of Radiology.

Objectives: Tissue stiffness can guide medical diagnoses and is exploited as an imaging contrast in elastography. However, different elastography devices show different liver stiffness values in the same subject, hindering comparison of values and establishment of system-independent thresholds for disease detection. There is a need for standardized phantoms that specifically address the viscosity-related dispersion of stiffness over frequency. To improve standardization of clinical elastography across devices and platforms including ultrasound and magnetic resonance imaging (MRI), a comprehensively characterized phantom is introduced that mimics the dispersion of stiffness of the human liver and can be generated reproducibly.

Materials And Methods: The phantom was made of linear polymerized polyacrylamide (PAAm) calibrated to the viscoelastic properties of healthy human liver in vivo as reported in the literature. Stiffness dispersion was analyzed using the 2-parameter springpot model fitted to the dispersion of shear wave speed of PAAm, which was measured by shear rheometry, ultrasound-based time-harmonic elastography, clinical magnetic resonance elastography (MRE), and tabletop MRE in the frequency range of 5 to 3000 Hz. Imaging parameters for ultrasound and MRI, reproducibility, aging behavior, and temperature dependency were assessed. In addition, the frequency bandwidth of shear wave speed of clinical elastography methods (Aplio i900, Canon; Acuson Sequoia, Siemens; FibroScan, EchoSense) was characterized.

Results: Within the entire frequency range analyzed in this study, the PAAm phantom reproduced well the stiffness dispersion of human liver in vivo despite its fluid properties under static loading (springpot stiffness parameter, 2.14 [95% confidence interval, 2.08-2.19] kPa; springpot powerlaw exponent, 0.367 [95% confidence interval, 0.362-0.373]). Imaging parameters were close to those of liver in vivo with only slight variability in stiffness values of 0.5% (0.4%, 0.6%), 4.1% (3.9%, 4.5%), and -0.63% (-0.67%, -0.58%), respectively, between batches, over a 6-month period, and per °C increase in temperature.

Conclusions: The liquid-liver phantom has useful properties for standardization and development of liver elastography. First, it can be used across clinical and experimental elastography devices in ultrasound and MRI. Second, being a liquid, it can easily be adapted in size and shape to specific technical requirements, and by adding inclusions and scatterers. Finally, because the phantom is based on noncrosslinked linear PAAm constituents, it is easy to produce, indicating potential widespread use among researchers and vendors to standardize liver stiffness measurements.
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http://dx.doi.org/10.1097/RLI.0000000000000862DOI Listing
August 2022

Effects of Atrial Fibrillation on the Human Ventricle.

Circ Res 2022 04 23;130(7):994-1010. Epub 2022 Feb 23.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany (S.P., M.K., T.S., M.P., T.K., A.P., L.S.M., S. Sossalla).

Rationale: Atrial fibrillation (AF) and heart failure often coexist, but their interaction is poorly understood. Clinical data indicate that the arrhythmic component of AF may contribute to left ventricular (LV) dysfunction.

Objective: This study investigates the effects and molecular mechanisms of AF on the human LV.

Methods And Results: Ventricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm or rate-controlled AF was studied. LV myocardium from patients with sinus rhythm and patients with AF showed no differences in fibrosis. In functional studies, systolic Ca transient amplitude of LV cardiomyocytes was reduced in patients with AF, while diastolic Ca levels and Ca transient kinetics were not statistically different. These results were confirmed in LV cardiomyocytes from nonfailing donors with sinus rhythm or AF. Moreover, normofrequent AF was simulated in vitro using arrhythmic or rhythmic pacing (both at 60 bpm). After 24 hours of AF-simulation, human LV cardiomyocytes from nonfailing donors showed an impaired Ca transient amplitude. For a standardized investigation of AF-simulation, human iPSC-cardiomyocytes were tested. Seven days of AF-simulation caused reduced systolic Ca transient amplitude and sarcoplasmic reticulum Ca load likely because of an increased diastolic sarcoplasmic reticulum Ca leak. Moreover, cytosolic Na concentration was elevated and action potential duration was prolonged after AF-simulation. We detected an increased late Na current as a potential trigger for the detrimentally altered Ca/Na-interplay. Mechanistically, reactive oxygen species were higher in the LV of patients with AF. CaMKII (Ca/calmodulin-dependent protein kinase IIδc) was found to be more oxidized at Met281/282 in the LV of patients with AF leading to an increased CaMKII activity and consequent increased RyR2 phosphorylation. CaMKII inhibition and ROS scavenging ameliorated impaired systolic Ca handling after AF-simulation.

Conclusions: AF causes distinct functional and molecular remodeling of the human LV. This translational study provides the first mechanistic characterization and the potential negative impact of AF in the absence of tachycardia on the human ventricle.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8963444PMC
April 2022

Self-supported amorphous TaN(O)/nickel foam thin film as an advanced electrocatalyst for hydrogen evolution reaction.

Chem Commun (Camb) 2022 Mar 8;58(20):3310-3313. Epub 2022 Mar 8.

Laboratory for High Performance Ceramics, Department of Metallurgical and Materials Engineering, Indian Institute of Technology-Madras (IIT Madras), Chennai 600036, India.

Chemical vapor deposited (CVD) amorphous tantalum-oxy nitride film on porous three-dimensional (3D) nickel foam (TaN(O)/NF) utilizing tantalum precursor, tris(diethylamino)(ethylimino)tantalum(V), ([Ta(NEt)(NEt)]) with preformed Ta-N bonds is reported as a potential self-supported electrocatalyst for hydrogen evolution reaction (HER). The morphological analyses revealed the formation of thin film of core-shell structured TaN(O) coating ( 236 nm) on NF. In 0.5 M HSO, TaN(O)/NF exhibited enhanced HER activity with a low onset potential as compared to the bare NF (-50 mV -166 mV). The TaN(O)/NF samples also displayed higher current density (-11.08 mA cm -3.36 mA cm at 400 mV), lower Tafel slope (151 mV dec 179 mV dec) and lower charge transfer resistance exemplifying the advantage of TaN(O) coating towards enhanced HER performance. The enhanced HER catalytic activity is attributed to the synergistic effect between the amorphous TaN(O) film and the nickel foam.
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http://dx.doi.org/10.1039/d2cc00151aDOI Listing
March 2022

Kidney Perfusion in Contrast-Enhanced Ultrasound (CEUS) Correlates with Renal Function in Living Kidney Donors.

J Clin Med 2022 Feb 1;11(3). Epub 2022 Feb 1.

Department of Urology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany.

Contrast-enhanced ultrasound (CEUS) is a widely used diagnostic tool for analyzing perfusion and characterizing lesions in several organs. However, to date, it has not been sufficiently investigated whether there is an association between CEUS findings and kidney function. This study aimed at identifying the potential relationship between kidney function and the renal perfusion status determined by CEUS in living kidney donors. A total of 30 living kidney donors examined between April 2018 and March 2020 were included in the study. All patients underwent various diagnostic procedures for evaluation of renal function. CEUS was performed in all 30 donors one day before nephrectomy. Kidney perfusion was quantified using a postprocessing tool (VueBox, Bracco Imaging). Various perfusion parameters were subsequently analyzed and compared with the results of the other methods used to evaluate kidney function. Of all parameters, mean signal intensity (MeanLin) had the strongest correlation, showing significant correlations with eGFR (CG) (r = -0.345; = 0.007) and total kidney volume (r = -0.409; = 0.001). While there was no significant correlation between any perfusion parameter and diethylenetriaminepentaacetic acid (DTPA), we detected a significant correlation between MeanLin and DTPA (r = -0.502; = 0.005) in the subgroup of normal-weight donors. The results indicate that signal intensity in CEUS is associated with kidney function in normal-weight individuals. Body mass index (BMI) may be a potential confounder of signal intensity in CEUS. Thus, more research is needed to confirm these results in larger study populations.
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http://dx.doi.org/10.3390/jcm11030791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836871PMC
February 2022

Reversible cerebral vasoconstriction syndrome after intravenous iron substitution: a case report.

J Neurol 2022 07 13;269(7):3918-3922. Epub 2022 Feb 13.

Department of Neurology, University Hospital Munich, Ludwig-Maximilians Universität München, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany.

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http://dx.doi.org/10.1007/s00415-022-11011-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9217862PMC
July 2022

Treatment outcome and identification of factors influencing overall survival after Lu-177-PSMA-617 radioligand therapy in metastatic prostate cancer.

Nuklearmedizin 2022 Feb 16;61(1):25-32. Epub 2021 Dec 16.

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Köln, Köln (Cologne), Germany.

Objective: To examine the clinical benefit of Lu-177-PSMA-617 radioligand therapy for patients with metastatic castration-resistant prostate cancer (mCRPC).

Patients And Methods: Between November 2014 and December 2018, a total of 56 consecutive patients (median age 69.5 years; range 55-84 years) with mCRPC were included in this retrospective analysis. Patients received between 1 and 4 therapy cycles with a mean activity of 6.8 GBq per cycle. Biochemical response was evaluated using Prostate Cancer Working Group Criteria 3 (PCWG 3). Survival was assessed using Kaplan-Meier estimates and Cox proportional hazards regression analysis. This retrospective study was approved by the local ethics committee.

Results: A total of 139 treatment cycles with Lu-177-PSMA-617 were performed. A decline of 50% or more of prostate-specific antigen (PSA) level occurred in 54% and a PSA decline of any amount in 65% of patients. The estimated median overall survival (OS) was 16 months, in the chemotherapy subgroup 14 months. A longer OS was associated with a PSA-decline ≥50%, more than 2 cycles of therapy, cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l]. These identified predictors remained significant on uni- and multivariate Cox regression analysis. Moreover, 40% of the patients who were non-responders after the first therapy cycle turned into responders after the second one.

Conclusion: PSA-decline ≥50%, a cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l] were identified as key predictors of prolonged OS in patients with mCRPC. In contrast rapid clinical deterioration mostly due to skeletal carcinomatosis resulted in early treatment failure.
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http://dx.doi.org/10.1055/a-1670-9500DOI Listing
February 2022

Opposite effects of the triple target (DNA-PK/PI3K/mTOR) inhibitor PI-103 on the radiation sensitivity of glioblastoma cell lines proficient and deficient in DNA-PKcs.

BMC Cancer 2021 Nov 11;21(1):1201. Epub 2021 Nov 11.

Department of Radiation Oncology, University Hospital of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.

Background: Radiotherapy is routinely used to combat glioblastoma (GBM). However, the treatment efficacy is often limited by the radioresistance of GBM cells.

Methods: Two GBM lines MO59K and MO59J, differing in intrinsic radiosensitivity and mutational status of DNA-PK and ATM, were analyzed regarding their response to DNA-PK/PI3K/mTOR inhibition by PI-103 in combination with radiation. To this end we assessed colony-forming ability, induction and repair of DNA damage by γH2AX and 53BP1, expression of marker proteins, including those belonging to NHEJ and HR repair pathways, degree of apoptosis, autophagy, and cell cycle alterations.

Results: We found that PI-103 radiosensitized MO59K cells but, surprisingly, it induced radiation resistance in MO59J cells. Treatment of MO59K cells with PI-103 lead to protraction of the DNA damage repair as compared to drug-free irradiated cells. In PI-103-treated and irradiated MO59J cells the foci numbers of both proteins was higher than in the drug-free samples, but a large portion of DNA damage was quickly repaired. Another cell line-specific difference includes diminished expression of p53 in MO59J cells, which was further reduced by PI-103. Additionally, PI-103-treated MO59K cells exhibited an increased expression of the apoptosis marker cleaved PARP and increased subG1 fraction. Moreover, irradiation induced a strong G2 arrest in MO59J cells (~ 80% vs. ~ 50% in MO59K), which was, however, partially reduced in the presence of PI-103. In contrast, treatment with PI-103 increased the G2 fraction in irradiated MO59K cells.

Conclusions: The triple-target inhibitor PI-103 exerted radiosensitization on MO59K cells, but, unexpectedly, caused radioresistance in the MO59J line, lacking DNA-PK. The difference is most likely due to low expression of the DNA-PK substrate p53 in MO59J cells, which was further reduced by PI-103. This led to less apoptosis as compared to drug-free MO59J cells and enhanced survival via partially abolished cell-cycle arrest. The findings suggest that the lack of DNA-PK-dependent NHEJ in MO59J line might be compensated by DNA-PK independent DSB repair via a yet unknown mechanism.
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http://dx.doi.org/10.1186/s12885-021-08930-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582108PMC
November 2021

Paracelsus' legacy in the faunal realm: Drugs deriving from animal toxins.

Drug Discov Today 2022 02 19;27(2):567-575. Epub 2021 Oct 19.

Center of Organic and Medicinal Chemistry, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences ZHAW, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland. Electronic address:

Given the vast number of venomous and poisonous animals, it is surprising that only relatively few animal-derived toxins have been explored and made their way into marketed drugs or are being investigated in ongoing clinical trials. In this review, we highlight marketed drugs deriving from animal toxins as well as ongoing clinical trials and preclinical investigations in the field. We emphasize that more attention should be paid to the rich supply of candidates that nature provides as valuable starting points for addressing serious unmet medical needs.
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http://dx.doi.org/10.1016/j.drudis.2021.10.003DOI Listing
February 2022

Inhibition of USP28 overcomes Cisplatin-resistance of squamous tumors by suppression of the Fanconi anemia pathway.

Cell Death Differ 2022 03 5;29(3):568-584. Epub 2021 Oct 5.

Protein Stability and Cancer Group, Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany.

Squamous cell carcinomas (SCC) frequently have an exceptionally high mutational burden. As consequence, they rapidly develop resistance to platinum-based chemotherapy and overall survival is limited. Novel therapeutic strategies are therefore urgently required. SCC express ∆Np63, which regulates the Fanconi Anemia (FA) DNA-damage response in cancer cells, thereby contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity. This phosphorylation event is required to positively regulate the DNA damage repair in SCC by stabilizing ∆Np63. Knock-down or inhibition of USP28 by a specific inhibitor weakens the ability of SCC to cope with DNA damage during platin-based chemotherapy. Hence, our study presents a novel mechanism by which ∆Np63 expressing SCC can be targeted to overcome chemotherapy resistance. Limited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ∆Np63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-∆Np63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.
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http://dx.doi.org/10.1038/s41418-021-00875-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8901929PMC
March 2022
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