Publications by authors named "Jan Forster"

18 Publications

  • Page 1 of 1

Statins affect cancer cell plasticity with distinct consequences for tumor progression and metastasis.

Cell Rep 2021 Nov;37(8):110056

Department of Medical Oncology, West German Cancer Center, University Hospital Essen at the University Duisburg-Essen, Duisburg, Germany; German Cancer Consortium (DKTK) partner site Essen, Essen, Germany. Electronic address:

Statins are among the most commonly prescribed drugs, and around every fourth person above the age of 40 is on statin medication. Therefore, it is of utmost clinical importance to understand the effect of statins on cancer cell plasticity and its consequences to not only patients with cancer but also patients who are on statins. Here, we find that statins induce a partial epithelial-to-mesenchymal transition (EMT) phenotype in cancer cells of solid tumors. Using a comprehensive STRING network analysis of transcriptome, proteome, and phosphoproteome data combined with multiple mechanistic in vitro and functional in vivo analyses, we demonstrate that statins reduce cellular plasticity by enforcing a mesenchymal-like cell state that increases metastatic seeding ability on one side but reduces the formation of (secondary) tumors on the other due to heterogeneous treatment responses. Taken together, we provide a thorough mechanistic overview of the consequences of statin use for each step of cancer development, progression, and metastasis.
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http://dx.doi.org/10.1016/j.celrep.2021.110056DOI Listing
November 2021

Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer.

Transl Oncol 2021 Nov 17;15(1):101279. Epub 2021 Nov 17.

German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, Essen 45122, Germany; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen 45122, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. Electronic address:

Background: Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility.

Methods: We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays.

Results: A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay (cfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in cfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status.

Conclusion: Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoring.
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http://dx.doi.org/10.1016/j.tranon.2021.101279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605355PMC
November 2021

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.

Nat Commun 2021 09 17;12(1):5505. Epub 2021 Sep 17.

Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8 T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.
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http://dx.doi.org/10.1038/s41467-021-25728-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448826PMC
September 2021

Tinnitus development is associated with synaptopathy of inner hair cells in Mongolian gerbils.

Eur J Neurosci 2021 08 28;54(3):4768-4780. Epub 2021 Jun 28.

Experimental Otolaryngology, Department of Otorhinolaryngology, Head and Neck Surgery, Friedrich Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Human hearing loss (HL) is often accompanied by comorbidities like tinnitus, which is affecting up to 15% of the adult population. Rodent animal studies could show that tinnitus may not only be a result of apparent HL due to cochlear hair cell damage but can also be a consequence of synaptopathy at the inner hair cells (IHCs) already induced by moderate sound traumata. Here, we investigate synaptopathy previously shown in mice in our animal model, the Mongolian gerbil, and relate it to behavioral signs of tinnitus. Tinnitus was induced by a mild monaural acoustic trauma leading to monaural noise induced HL in the animals, quantified by auditory brainstem response (ABR) audiometry. Behavioral signs of tinnitus percepts were detected by measurement of prepulse inhibition of the acoustic startle response in a gap-noise paradigm. Fourteen days after trauma, the cochleae of both ears were isolated, and IHC synapses were counted within several spectral regions of the cochlea. Behavioral signs of tinnitus were only found in animals with IHC synaptopathy, independent of type of HL. On the other hand, animals with apparent HL but without behavioral signs of tinnitus showed a reduction in amplitudes of ABR waves I&II but no significant changes in the number of synapses at the IHC. We conclude-in line with the literature-that HL is caused by damage to the IHC or by other reasons but that the development of tinnitus, at least in our animal model, is closely linked to synaptopathy at the IHC.
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http://dx.doi.org/10.1111/ejn.15334DOI Listing
August 2021

Sustainable data analysis with Snakemake.

F1000Res 2021 18;10:33. Epub 2021 Jan 18.

Algorithms for reproducible bioinformatics, Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Data analysis often entails a multitude of heterogeneous steps, from the application of various command line tools to the usage of scripting languages like R or Python for the generation of plots and tables. It is widely recognized that data analyses should ideally be conducted in a reproducible way. Reproducibility enables technical validation and regeneration of results on the original or even new data. However, reproducibility alone is by no means sufficient to deliver an analysis that is of lasting impact (i.e., sustainable) for the field, or even just one research group. We postulate that it is equally important to ensure adaptability and transparency. The former describes the ability to modify the analysis to answer extended or slightly different research questions. The latter describes the ability to understand the analysis in order to judge whether it is not only technically, but methodologically valid. Here, we analyze the properties needed for a data analysis to become reproducible, adaptable, and transparent. We show how the popular workflow management system Snakemake can be used to guarantee this, and how it enables an ergonomic, combined, unified representation of all steps involved in data analysis, ranging from raw data processing, to quality control and fine-grained, interactive exploration and plotting of final results.
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http://dx.doi.org/10.12688/f1000research.29032.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114187PMC
June 2021

Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis.

Oncogenesis 2020 Nov 19;9(11):102. Epub 2020 Nov 19.

Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial-mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.
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http://dx.doi.org/10.1038/s41389-020-00286-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677369PMC
November 2020

Plasma Next Generation Sequencing and Droplet Digital-qPCR-Based Quantification of Circulating Cell-Free RNA for Noninvasive Early Detection of Cancer.

Cancers (Basel) 2020 Feb 4;12(2). Epub 2020 Feb 4.

German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.

Early detection of cancer holds high promise for reducing cancer-related mortality. Detection of circulating tumor-specific nucleic acids holds promise, but sensitivity and specificity issues remain with current technology. We studied cell-free RNA (cfRNA) in patients with non-small cell lung cancer (NSCLC; n = 56 stage IV, n = 39 stages I-III), pancreatic cancer (PDAC, n = 20 stage III), malignant melanoma (MM, n = 12 stage III-IV), urothelial bladder cancer (UBC, n = 22 stage II and IV), and 65 healthy controls by means of next generation sequencing (NGS) and real-time droplet digital PCR (RT-ddPCR). We identified 192 overlapping upregulated transcripts in NSCLC and PDAC by NGS, more than 90% of which were noncoding. Previously reported transcripts (e.g., HOTAIRM1) were identified. Plasma cfRNA transcript levels of POU6F2-AS2 discriminated NSCLC from healthy donors (AUC = 0.82 and 0.76 for stages IV and I-III, respectively) and significantly associated ( = 0.017) with the established tumor marker Cyfra 21-1. cfRNA yield and POU6F2-AS transcript abundance discriminated PDAC patients from healthy donors (AUC = 1.0). POU6F2-AS2 transcript was significantly higher in MM ( = 0.044). In summary, our findings support further validation of cfRNA detection by RT-ddPCR as a biomarker for early detection of solid cancers.
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http://dx.doi.org/10.3390/cancers12020353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073169PMC
February 2020

Right ventricular structure and function in senior and academy elite footballers.

Scand J Med Sci Sports 2018 Dec 2;28(12):2617-2624. Epub 2018 Sep 2.

Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK.

Aims: Right ventricular (RV) adaptation is a common finding in the athlete's heart. The aim of this study was to establish the extent of RV structural and functional adaptation in elite and academy professional footballers compared to age-matched controls.

Methods And Results: A total of 100 senior and 100 academy elite footballers and 20 senior and 19 academy age-matched controls were recruited. All participants underwent 2D, Doppler, tissue Doppler, and strain (ε) echocardiography of the right heart. Structural indices were derived and indexed allometrically for individual differences in body surface area. Standard RV function was assessed alongside peak RV ε and strain rate (SR). Senior football players had larger scaled RV structural parameters than academy players for the RV outflow (RVOT ) (32.7 ± 4.2 and 29.5 ± 4.0 mm(m ) , P < 0.001), the proximal RV outflow (RVOT ) (26.6 ± 3.5 and 24.7 ± 3.9 mm(m ) , P < 0.001), the basal RV inflow (RVD ) (33.1 ± 4.1 and 30.7 ± 3.2 mm(m ) , P = 0.020), RV length (RVD ) (66.5 ± 6.1 and 62.9 ± 5.1 mm(m ) , P < 0.001), and RV diastolic area (RVD ) (16.9 ± 2.6 and 15.7 ± 2.6 mm(m ) , P < 0.001). Both academy and senior football players demonstrated larger scaled structural RV parameters in comparison with age-matched controls. Systolic SR (SRS) was lower in the senior players compared to academy players in the mid (-1.52 ± 0.49 and -1.41 ± 0.34 L/s, P = 0.019) and apical (-1.97 ± 0.74 and -1.72 ± 0.42 L/s, P = 0.025) wall regions, respectively.

Conclusion: Right ventricular structural adaptation occurs in both senior and academy football players with senior players having larger RV dimensions. Although senior players have slightly lower peak SRS than academy players, all global ε and SR are within normal ranges.
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http://dx.doi.org/10.1111/sms.13272DOI Listing
December 2018

Improved microscale cultivation of for clonal screening.

Fungal Biol Biotechnol 2018 3;5. Epub 2018 May 3.

1Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany.

Background: Expanding the application of technical enzymes, e.g., in industry and agriculture, commands the acceleration and cost-reduction of bioprocess development. Microplates and shake flasks are massively employed during screenings and early phases of bioprocess development, although major drawbacks such as low oxygen transfer rates are well documented. In recent years, miniaturization and parallelization of stirred and shaken bioreactor concepts have led to the development of novel microbioreactor concepts. They combine high cultivation throughput with reproducibility and scalability, and represent promising tools for bioprocess development.

Results: Parallelized microplate cultivation of the eukaryotic protein production host was applied effectively to support miniaturized phenotyping of clonal libraries in batch as well as fed-batch mode. By tailoring a chemically defined growth medium, we show that growth conditions are scalable from microliter to 0.8 L lab-scale bioreactor batch cultivation with different carbon sources. Thus, the set-up allows for a rapid physiological comparison and preselection of promising clones based on online data and simple offline analytics. This is exemplified by screening a clonal library of constitutively expressing AppA phytase from . The protocol was further modified to establish carbon-limited conditions by employing enzymatic substrate-release to achieve screening conditions relevant for later protein production processes in fed-batch mode.

Conclusion: The comparison of clonal rankings under batch and fed-batch-like conditions emphasizes the necessity to perform screenings under process-relevant conditions. Increased biomass and product concentrations achieved after fed-batch microscale cultivation facilitates the selection of top producers. By reducing the demand to conduct laborious and cost-intensive lab-scale bioreactor cultivations during process development, this study will contribute to an accelerated development of protein production processes.
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http://dx.doi.org/10.1186/s40694-018-0053-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932850PMC
May 2018

The trade-off of availability and growth inhibition through copper for the production of copper-dependent enzymes by Pichia pastoris.

BMC Biotechnol 2016 Feb 20;16:20. Epub 2016 Feb 20.

Centre for Biotechnology, Anna University, Sardar Patel Road, Guindy, Chennai, 600025, India.

Background: Copper is an essential chemical element for life as it is a part of prosthetic groups of enzymes including super oxide dismutase and cytochrome c oxidase; however, it is also toxic at high concentrations. Here, we present the trade-off of copper availability and growth inhibition of a common host used for copper-dependent protein production, Pichia pastoris.

Results: At copper concentrations ranging from 0.1 mM (6.35 mg/L) to 2 mM (127 mg/L), growth rates of 0.25 h(-1) to 0.16 h(-1) were observed with copper uptake of as high as 20 mgcopper/gCDW. The intracellular copper content was estimated by subtracting the copper adsorbed on the cell wall from the total copper concentration in the biomass. Higher copper concentrations led to stronger cell growth retardation and, at 10 mM (635 mg/L) and above, to growth inhibition. To test the determined copper concentration range for optimal recombinant protein production, a laccase gene from Aspergillus clavatus [EMBL: EAW07265.1] was cloned under the control of the constitutive glyceraldehyde-3-phosphate (GAP) dehydrogenase promoter for expression in P. pastoris. Notably, in the presence of copper, laccase expression improved the specific growth rate of P. pastoris. Although copper concentrations of 0.1 mM and 0.2 mM augmented laccase expression 4 times up to 3 U/mL compared to the control (0.75 U/mL), while higher copper concentrations resulted in reduced laccase production. An intracellular copper content between 1 and 2 mgcopper/gCDW was sufficient for increased laccase activity. The physiology of the yeast could be excluded as a reason for the stop of laccase production at moderate copper concentrations as no flux redistribution could be observed by (13)C-metabolic flux analysis.

Conclusion: Copper and its pivotal role to sustain cellular functions is noteworthy. However, knowledge on its cellular accumulation, availability and distribution for recombinant protein production is limited. This study attempts to address one such challenge, which revealed the fact that intracellular copper accumulation influenced laccase production and should be considered for high protein expression of copper-dependent enzymes when using P. pastoris. The results are discussed in the context of P. pastoris as a general host for copper -dependent enzyme production.
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http://dx.doi.org/10.1186/s12896-016-0251-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761204PMC
February 2016

A blueprint of the amino acid biosynthesis network of hemiascomycetes.

FEMS Yeast Res 2014 Nov 13;14(7):1090-100. Epub 2014 Oct 13.

Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany.

The structure and regulation of biosynthesis pathways in Saccharomyces cerevisiae have been detailed extensively. For other hemiascomycetes, genomic sequences are primarily available, whereas biochemical information on them is scarce. The resulting biochemical networks that are used for research in basic science and biotechnology are often biased by data from S. cerevisiae, assuming that there are often implicitly conserved structures between species. We examined the structure of the amino acid biosynthesis network in nine hemiascomycetes, spanning the phylogenetic clade. Differences in the genetic inventory included the presence and absence of isoenzymes and compartmentation of the pathways. Notably, no two hemiascomycetes had identical genetic inventories. For example, the lack of the mitochondrial αIPMS isoenzyme and presence of only one copy of the BCAA aminotransferase in Pichia pastoris indicate a disparately compartmented leucine biosynthesis pathway. Our findings suggest that αIPMS and BCAA aminotransferase are solely located in the cytosol of P. pastoris, requiring correction of the leucine biosynthesis pathway layout in this species. Our results argue for careful use of information from S. cerevisiae and for joint efforts to fill the knowledge gaps in other species. Such analysis will lead to contributions in biotechnology disciplines, such as protein production and compartment engineering.
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http://dx.doi.org/10.1111/1567-1364.12205DOI Listing
November 2014

3D Echo systematically underestimates right ventricular volumes compared to cardiovascular magnetic resonance in adult congenital heart disease patients with moderate or severe RV dilatation.

J Cardiovasc Magn Reson 2011 Dec 8;13:78. Epub 2011 Dec 8.

Division of Medicine (Cardiology), Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada.

Background: Three dimensional echo is a relatively new technique which may offer a rapid alternative for the examination of the right heart. However its role in patients with non-standard ventricular size or anatomy is unclear. This study compared volumetric measurements of the right ventricle in 25 patients with adult congenital heart disease using both cardiovascular magnetic resonance (CMR) and three dimensional echocardiography.

Methods: Patients were grouped by diagnosis into those expected to have normal or near-normal RV size (patients with repaired coarctation of the aorta) and patients expected to have moderate or worse RV enlargement (patients with repaired tetralogy of Fallot or transposition of the great arteries). Right ventricular end diastolic volume, end systolic volume and ejection fraction were compared using both methods with CMR regarded as the reference standard

Results: Bland-Altman analysis of the 25 patients demonstrated that for both RV EDV and RV ESV, there was a significant and systematic under-estimation of volume by 3D echo compared to CMR. This bias led to a mean underestimation of RV EDV by -34% (95%CI: -91% to + 23%). The degree of underestimation was more marked for RV ESV with a bias of -42% (95%CI: -117% to + 32%). There was also a tendency to overestimate RV EF by 3D echo with a bias of approximately 13% (95% CI -52% to +27%).

Conclusions: Statistically significant and clinically meaningful differences in volumetric measurements were observed between the two techniques. Three dimensional echocardiography does not appear ready for routine clinical use in RV assessment in congenital heart disease patients with more than mild RV dilatation at the current time.
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http://dx.doi.org/10.1186/1532-429X-13-78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283510PMC
December 2011

Altered left ventricular diastolic filling following a marathon is a reproducible phenomenon.

Int J Cardiol 2007 Oct 11;122(1):87-9. Epub 2007 Jan 11.

The present study examined the reproducibility of alterations in left ventricular function and cardiac biomarkers in a cohort of athletes following two marathons, one year apart. Eight participants in the 2004 and 2005 London Marathons were tested pre- and post-race via echocardiography and humoral analysis. Reductions in diastolic filling, unrelated to loading or heart rate, following both marathons were reproducible within individuals, which may be a function of exercise duration. In contrast, exercise-induced cardiac troponin release was inconsistent.
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http://dx.doi.org/10.1016/j.ijcard.2006.11.042DOI Listing
October 2007

The impact of marathon running upon ventricular function as assessed by 2D, Doppler, and tissue-Doppler echocardiography.

Echocardiography 2006 Sep;23(8):635-41

Cardiac Ultrasound Department, Leeds General Infirmary, Leeds, UK.

The impact of prolonged exercise upon right ventricular (RV) function is poorly understood and to date no studies have utilized tissue-Doppler imaging (TDI). Thirty-five marathon runners (age range 18-50 years) volunteered for the study. Two-dimensional, pulsed Doppler, and TDI studies were performed one day before and immediately following race completion. Right and left ventricular (LV) longitudinal TDI myocardial velocities were acquired from the tricuspid annulus and mitral annulus, providing velocity data during systole (S'), early diastole (E'), and late diastole (A'). Transtricuspid and transmitral, early diastolic (E), and late diastolic (A) velocities and ratios were assessed using conventional pulsed-wave Doppler. RV and LV fractional area changes (FAC) were calculated from RV and LV end-diastolic and end-systolic areas recorded from 2D scans in a subsample (n = 23). RV myocardial velocities were unchanged pre-post race in S' (21.1 +/- 2.7 to 21.7 +/- 4.5 cm s(-1), P > 0.05), reduced in E' (23.3 +/- 3.5 to 19.9 +/- 5.3 cm s(-1), P < 0.05), increased in A' (19.1 +/- 3.6 to 23.7 +/- 6.8 cm s(-1), P < 0.05) with a resultant decline in E'/A' (1.28 +/- 0.36 to 0.94 +/- 0.45, P < 0.05). This pattern of data was mirrored in the LV. Similarly both pulsed-Doppler tricuspid and mitral E/A ratios decreased from pre- to postrace (P < 0.05). FAC for the RV and LV were unaltered postrace (P > 0.05). The impact of differing age, finishing time (173-330 min), hemodynamic loading and heart rate upon RV and LV function pre- to postrace was negligible. In conclusion, TDI and 2D data, for both the RV and LV demonstrated little change in systolic function after a marathon race. Conversely, a reduction in diastolic function was observed in both ventricles for which a mechanism has yet to be deduced.
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http://dx.doi.org/10.1111/j.1540-8175.2006.00282.xDOI Listing
September 2006

Novel application of flow propagation velocity and ischaemia-modified albumin in analysis of postexercise cardiac function in man.

Exp Physiol 2006 May 23;91(3):511-9. Epub 2006 Jan 23.

Centre for Sports Medicine and Human Performance, Brunel University, London, UK.

The present study employed novel echocardiographic tools and cardiac markers to obtain a greater understanding of the aetiology and time course of altered cardiac function and cardiac damage following prolonged exercise and, in particular, the possible role of transient ischaemia within these phenomena. Fourteen runners in the 2004 London Marathon were assessed pre-, immediately post-, 1 h post- and 24 h postcompletion of the race. Left ventricular function was examined echocardiographically using 2-D, M-mode, tissue Doppler imaging and flow propagation velocity (Vp). Venous blood samples were analysed for N-terminal pro-B-type natriuretic peptide (proBNP), cardiac troponin T (cTnT) and ischaemia-modified albumin (IMA). Left ventricular (LV) diastolic filling was altered on completion of the race, as indicated by significant decreases in mean early to late diastolic myocardial wave (E':A') ratio and Vp (from 1.82 +/- 0.9 to 1.32 +/- 0.32, and from 67.5 +/- 9.3 to 60.2 +/- 8.2 cm s(-1), respectively, P < 0.05), accompanied by an increase in proBNP (from 21.6 +/- 11 to 47.08 +/- 19.5 pg l(-1), P < 0.05). The observed reduction in LV diastolic filling following completion of a marathon, unrelated to changes in heart rate or loading parameters, indicates an intrinsically mediated change in diastolic filling. Exercise-induced elevations in cTnT in nine individuals (range, 0.023-0.37 microg l(-1)) were indicative of minor cardiac damage. A significant reduction in IMA was observed after the marathon (from 63.68 +/- 9.83 to 44.94 +/- 16.13 Um l(-1), P < 0.05), unrelated to the alterations in cardiac function, proBNP or cTnT. The absence of an elevation in IMA suggests that exercise-induced myocardial ischaemia did not occur and therefore could not explain the changes in cardiac function or biomarkers. Future studies in this area should investigate alternative diagnostic tools for the detection of transient ischaemia, and other potential mechanisms, in order to extend the understanding of this phenomenon.
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http://dx.doi.org/10.1113/expphysiol.2005.032631DOI Listing
May 2006

Mitral annular myocardial velocity assessment of segmental left ventricular diastolic function after prolonged exercise in humans.

J Physiol 2005 Nov 18;569(Pt 1):305-13. Epub 2005 Aug 18.

Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, UK.

We assessed segmental and global left ventricular (LV) diastolic function via tissue-Doppler imaging (TDI) as well as Doppler flow variables before and after a marathon race to extend our knowledge of exercise-induced changes in cardiac function. Twenty-nine subjects (age 18-62 year) volunteered to participate and were assessed pre- and post-race. Measurements of longitudinal plane TDI myocardial diastolic velocities at five sites on the mitral annulus included peak early myocardial tissue velocity (E'), peak late (or atrial) myocardial tissue velocity (A') and the ratio E'/A'. Standard pulsed-wave Doppler transmitral and pulmonary vein flow indices were also recorded along with measurements of body mass, heart rate, blood pressures and cardiac troponin T (cTnT), a biomarker of myocyte damage. Pre- to post-race changes in LV diastolic function were analysed by repeated measures ANOVA. Delta scores for LV diastolic function were correlated with each other and alterations in indices of LV loading. Diastolic longitudinal segmental and mean TDI data were altered post-race such that the mean E'/A' ratio was significantly depressed (1.51 +/- 0.34 to 1.16 +/- 0.35, P < 0.05). Changes in segmental and global TDI data were not related to an elevated post-race HR, a decreased post-race pre-load or an elevated cTnT. The pulsed wave Doppler ratio of peak early transmitral flow velocity (E)/peak late (or atrial) flow velocity (A) was also significantly reduced post-race (1.75 +/- 0.46 to 1.05 +/- 0.30, P < 0.05); however, it was significantly correlated with post-race changes in heart rate. The lack of change in E/E' from pre- to post-race (3.4 +/- 0.8 and 3.3 +/- 0.7, respectively) suggests that the depression in diastolic function is likely to be due to altered relaxation of the left ventricle; however, the exact aetiology of this change remains to be determined.
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http://dx.doi.org/10.1113/jphysiol.2005.095588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1464215PMC
November 2005

A universal algorithm for an improved finite element mesh generation Mesh quality assessment in comparison to former automated mesh-generators and an analytic model.

Med Eng Phys 2005 Jun 19;27(5):383-94. Epub 2005 Jan 19.

Department of Neurosurgery, University of Tübingen, Hoppe-Seyler-Str. 3 D-72076 Tübingen, Germany.

The FE-modeling of complex anatomical structures is not solved satisfyingly so far. Voxel-based as opposed to contour-based algorithms allow an automated mesh generation based on the image data. Nonetheless their geometric precision is limited. We developed an automated mesh-generator that combines the advantages of voxel-based generation with improved representation of the geometry by displacement of nodes on the object-surface. Models of an artificial 3D-pipe-section and a skullbase were generated with different mesh-densities using the newly developed geometric, unsmoothed and smoothed voxel generators. Compared to the analytic calculation of the 3D-pipe-section model the normalized RMS error of the surface stress was 0.173-0.647 for the unsmoothed voxel models, 0.111-0.616 for the smoothed voxel models with small volume error and 0.126-0.273 for the geometric models. The highest element-energy error as a criterion for the mesh quality was 2.61x10(-2) N mm, 2.46x10(-2) N mm and 1.81x10(-2) N mm for unsmoothed, smoothed and geometric voxel models, respectively. The geometric model of the 3D-skullbase resulted in the lowest element-energy error and volume error. This algorithm also allowed the best representation of anatomical details. The presented geometric mesh-generator is universally applicable and allows an automated and accurate modeling by combining the advantages of the voxel-technique and of improved surface-modeling.
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http://dx.doi.org/10.1016/j.medengphy.2004.10.004DOI Listing
June 2005

Impact of marathon running on cardiac structure and function in recreational runners.

Clin Sci (Lond) 2005 Jan;108(1):73-80

Olympic Medical Institute, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK.

The present study examined the relationship between LV (left ventricular) function, markers of cardiac-specific damage and markers of oxidative stress in recreational runners following a marathon. Runners (n=52; 43 male and nine female; age, 35+/-10 years; height, 1.74+/-0.08 m; body mass, 75.9+/-8.9 kg) were assessed pre- and immediately post-marathon. LV function was assessed using standard M-mode two-dimensional Doppler echocardiography and TDI (tissue-Doppler imaging) echocardiography. Serum was analysed for cTnT (cardiac troponin-T), TEAC (Trolox equivalent antioxidant capacity; a measure of total antioxidant capacity), MDA (malondealdehyde) and 4-HNE (4-hydroxynonenal). A strong relationship was observed between standard and TDI echocardiography for all functional measures. Diastolic function was altered post-marathon characterized by a reduction in E (peak early diastolic filling: 0.79+/-0.11 compared with 0.64+/-0.16 cm/s; P<0.001), an increase in A (peak late diastolic filling: 0.48+/-0.11 compared with 0.60+/-0.12 cm/s; P<0.001) and a resultant decrease in E/A (ratio of E to A; 1.71+/-0.48 compared with 1.10+/-0.31; P<0.001). Ejection fraction remained unchanged post-marathon. Thirty-two runners presented with cTnT values above the lower limit of detection for the assay (0.01 microg/l), and 20 runners presented post-marathon with cTnT values above the acute myocardial infarction cut-off value (0.05 microg/l). No significant correlations were observed between cTnT and any functional measurements. MDA (2.90+/-1.58 compared with 3.59+/-1.47 micromol/l) and TEAC (1.80+/-0.12 compared with 1.89+/-0.21 mmol/l) were significantly increased post-marathon, but were unrelated to changes in function or cTnT. In conclusion, the present study demonstrated a reduction in diastolic function and widespread evidence of minimal cardiac damage following a marathon in recreational runners. The mechanism(s) underpinning the altered function and appearance of cTnT appear unrelated to reactive oxygen species.
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http://dx.doi.org/10.1042/CS20040186DOI Listing
January 2005
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