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Jenks, Andrew ; Vyse, Simon ; Wong, Jocelyn P. ; Kostaras, Eleftherios ; Keller, Deborah ; Burgoyne, Thomas ; Shoemark, Amelia ; Tsalikis, Athanasios ; Roche, Maike de la ; Michaelis, Martin ; Cinatl, Jindrich ; Huang, Paul H. ; Tanos, Barbara E.
Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.
Lenga, Lukas Fabian ; Lange, Marvin ; Martin, Simon S. ; Albrecht, Moritz Hans Ernst ; Booz, Christian ; Yel, Ibrahim ; Arendt, Christophe ; Vogl, Thomas J. ; Leithner, Doris
Objectives: To compare radiation dose and image quality of single-energy (SECT) and dual-energy (DECT) head and neck CT examinations performed with second- and third-generation dual-source CT (DSCT) in matched patient cohorts. Methods: 200 patients (mean age 55.1 ± 16.9 years) who underwent venous phase head and neck CT with a vendor-preset protocol were retrospectively divided into four equal groups (n = 50) matched by gender and BMI: second (Group A, SECT, 100-kV; Group B, DECT, 80/Sn140-kV), and third-generation DSCT (Group C, SECT, 100-kV; Group D, DECT, 90/Sn150-kV). Assess- ment of radiation dose was performed for an average scan length of 27 cm. Contrast-to-noise ratio measure- ments and dose-independent figure-of-merit calcu- lations of the submandibular gland, thyroid, internal jugular vein, and common carotid artery were analyzed quantitatively. Qualitative image parameters were evalu- ated regarding overall image quality, artifacts and reader confidence using 5-point Likert scales. Results: Effective radiation dose (ED) was not signifi- cantly different between SECT and DECT acquisition for each scanner generation (p = 0.10). Significantly lower effective radiation dose (p < 0.01) values were observed for third-generation DSCT groups C (1.1 ± 0.2 mSv) and D (1.0 ± 0.3 mSv) compared to second-generation DSCT groups A (1.8 ± 0.1 mSv) and B (1.6 ± 0.2 mSv). Figure-of- merit/contrast-to-noise ratio analysis revealed superior results for third-generation DECT Group D compared to all other groups. Qualitative image parameters showed non-significant differences between all groups (p > 0.06). Conclusion: Contrast-enhanced head and neck DECT can be performed with second- and third-generation DSCT systems without radiation penalty or impaired image quality compared with SECT, while third-generation DSCT is the most dose efficient acquisition method. Advances in knowledge: Differences in radiation dose between SECT and DECT of the dose-vulnerable head and neck region using DSCT systems have not been evaluated so far. Therefore, this study directly compares radiation dose and image quality of standard SECT and DECT protocols of second- and third-generation DSCT platforms.
Martin, Simon ; Kolaneci, Jetlir ; Czwikla, Rouben ; Booz, Christian ; Grünewald, Leon David ; Albrecht, Moritz Hans Ernst ; Thompson, Zachary M. ; Lenga, Lukas ; Yel, Ibrahim ; Vogl, Thomas J. ; Wichmann, Julian ; Koch, Vitali
Purpose: To investigate the diagnostic performance of noise-optimized virtual monoenergetic images (VMI+) in dual-energy CT (DECT) of portal vein thrombosis (PVT) compared to standard reconstructions. Method: This retrospective, single-center study included 107 patients (68 men; mean age, 60.1 ± 10.7 years) with malignant or cirrhotic liver disease and suspected PVT who had undergone contrast-enhanced portal-phase DECT of the abdomen. Linearly blended (M_0.6) and virtual monoenergetic images were calculated using both standard VMI and noise-optimized VMI+ algorithms in 20 keV increments from 40 to 100 keV. Quantitative measurements were performed in the portal vein for objective contrast-to-noise ratio (CNR) calculation. The image series showing the greatest CNR were further assessed for subjective image quality and diagnostic accuracy of PVT detection by two blinded radiologists. Results: PVT was present in 38 subjects. VMI+ reconstructions at 40 keV revealed the best objective image quality (CNR, 9.6 ± 4.3) compared to all other image reconstructions (p < 0.01). In the standard VMI series, CNR peaked at 60 keV (CNR, 4.7 ± 2.1). Qualitative image parameters showed the highest image quality rating scores for the 60 keV VMI+ series (median, 4) (p ≤ 0.03). The greatest diagnostic accuracy for the diagnosis of PVT was found for the 40 keV VMI+ series (sensitivity, 96%; specificity, 96%) compared to M_0.6 images (sensitivity, 87%; specificity, 92%), 60 keV VMI (sensitivity, 87%; specificity, 97%), and 60 keV VMI+ reconstructions (sensitivity, 92%; specificity, 97%) (p ≤ 0.01). Conclusions: Low-keV VMI+ reconstructions resulted in significantly improved diagnostic performance for the detection of PVT compared to other DECT reconstruction algorithms.
Vogl, Thomas J. ; Jaraysa, Yousef ; Martin, Simon S. ; Gruber-Rouh, Tatjana ; Savage, Rock H. ; Mohammed, Nour-Eldin Abdelrehim Nour-Eldin ; Mehmedovic, Amela
Purpose: The aim of this study was to prospectively compare the therapy response and safety of microwave (MWA) and radiofrequency ablation (RFA) for the treatment of liver metastases using a dual ablation system.
Methods: Fifty patients with liver metastases (23 men, mean age: 62.8 ± 11.8 years) were randomly assigned to MWA or RFA for thermal ablation using a one generator dual ablation system. Magnetic resonance imaging (MRI) was acquired before treatment and 24 h post ablation. The morphologic responses to treatment regarding size, volume, necrotic areas, and diffusion characteristics were evaluated by MRI. Imaging follow-up was obtained for one year in three months intervals, whereas clinical follow-up was obtained for two years in all patients.
Results: Twenty-six patients received MWA and 24 patients received RFA (mean diameter: 1.6 cm, MWA: 1.7 cm, RFA: 1.5 cm). The mean volume 24 h after ablation was 37.0 cm3 (MWA: 50.5 cm3, RFA: 22.9 cm3, P < 0.01). The local recurrence rate was 0% (0/26) in the MWA-group and 8.3% (2/24) in the RFA-group (P = 0.09). The rate of newly developed malignant formations was 38.0% (19/50) for both groups (MWA: 38.4%, RFA: 37.5%, P = 0.07). The overall survival rate was 70.0% (35/50) after two years (MWA: 76.9%, RFA: 62.5%, P = 0.60). No major complications were reported.
Conclusion: In conclusion, MWA and RFA are both safe and effective methods for the treatment of liver metastases with MWA generating greater volumes of ablation. No significant differences were found for overall survival, rate of neoplasm, or major complications between both groups.
Manning, Alistair J. ; Redington, Alison L. ; Say, Daniel ; O'Doherty, Simon ; Young, Dickon ; Simmonds, Peter G. ; Vollmer, Martin K. ; Mühle, Jens ; Arduini, Jgor ; Spain, Gerard ; Wisher, Adam ; Maione, Michela ; Schuck, Tanja J. ; Stanley, Kieran ; Reimann, Stefan ; Engel, Andreas ; Krummel, Paul B. ; Fraser, Paul J. ; Harth, Christina M. ; Salameh, Peter K. ; Weiss, Ray F. ; Gluckman, Ray ; Brown, Peter N. ; Watterson, John D. ; Arnold, Tim
National greenhouse gas inventories (GHGIs) are submitted annually to the United Nations Framework Convention on Climate Change (UNFCCC). They are estimated in compliance with Intergovernmental Panel on Climate Change (IPCC) methodological guidance using activity data, emission factors and facility-level measurements. For some sources, the outputs from these calculations are very uncertain. Inverse modelling techniques that use high-quality, long-term measurements of atmospheric gases have been developed to provide independent verification of national GHGIs. This is considered good practice by the IPCC as it helps national inventory compilers to verify reported emissions and to reduce emission uncertainty. Emission estimates from the InTEM (Inversion Technique for Emission Modelling) model are presented for the UK for the hydrofluorocarbons (HFCs) reported to the UNFCCC (HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-23, HFC-32, HFC-227ea, HFC-245fa, HFC-43-10mee and HFC-365mfc). These HFCs have high global warming potentials (GWPs), and the global background mole fractions of all but two are increasing, thus highlighting their relevance to the climate and a need for increasing the accuracy of emission estimation for regulatory purposes. This study presents evidence that the long-term annual increase in growth of HFC-134a has stopped and is now decreasing. For HFC-32 there is an early indication, its rapid global growth period has ended, and there is evidence that the annual increase in global growth for HFC-125 has slowed from 2018. The inverse modelling results indicate that the UK implementation of European Union regulation of HFC emissions has been successful in initiating a decline in UK emissions from 2018. Comparison of the total InTEM UK HFC emissions in 2020 with the average from 2009–2012 shows a drop of 35 %, indicating progress toward the target of a 79 % decrease in sales by 2030. The total InTEM HFC emission estimates (2008–2018) are on average 73 (62–83) % of, or 4.3 (2.7–5.9) Tg CO2-eq yr−1 lower than, the total HFC emission estimates from the UK GHGI. There are also significant discrepancies between the two estimates for the individual HFCs.
Manning, Alistair J. ; Redington, Alison L. ; Say, Daniel ; O'Doherty, Simon ; Young, Dickon ; Simonsen, Peter G. ; Vollmer, Martin K. ; Mühle, Jens ; Arduini, Jgor ; Spain, Gerard ; Wisher, Adam ; Maione, Michela ; Schuck, Tanja J. ; Stanley, Kieran ; Reimann, Stefan ; Engel, Andreas ; Krummel, Paul B. ; Fraser, Paul J. ; Harth, Christina M. ; Salameh, Peter K. ; Weiss, Ray F. ; Gluckman, Ray ; Brown, Peter N. ; Watterson, John D. ; Arnold, Tim
National Greenhouse Gas Inventories (GHGI) are submitted annually to the United Nations Framework Convention on Climate Change (UNFCCC). They are estimated in compliance with Intergovernmental Panel on Climate Change (IPCC) methodological guidance using activity data, emission factors and facility-level measurements. For some sources, the outputs from these calculations are very uncertain. Inverse modelling techniques that use high-quality, long-term measurements of atmospheric gases have been developed to provide independent verification of national GHGI. This is considered good practice by the IPCC as it helps national inventory compilers to verify reported emissions and to reduce emission uncertainty. Emission estimates from the InTEM (Inversion Technique for Emissions Modelling) model are presented for the UK for the hydrofluorocarbons (HFCs) reported to the UNFCCC (HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-23, HFC-32, HFC-227ea, HFC-245fa, HFC-43-10mee and HFC-365mfc). These HFCs have high Global Warming Potentials (GWPs) and the global background mole fractions of all but two are increasing, thus highlighting their relevance to the climate and a need for increasing the accuracy of emission estimation for regulatory purposes. This study presents evidence that the long-term annual increase in growth of HFC-134a has stopped and is now decreasing. For HFC-32 there is an early indication its rapid global growth period has ended, and there is evidence that the annual increase in global growth for HFC-125 has slowed from 2018. The inverse modelling results indicate that the UK implementation of European Union regulation of HFC emissions has been successful in initiating a decline in UK emissions in the since 2018. Comparison of the total InTEM UK HFC emissions in 2020 with the average from 2009–2012 shows a drop of 35%, indicating progress toward the target of a 79% decrease in sales by 2030. The total InTEM HFC emission estimates (2008–2018) are on average 73 (62–83)% of, or 4.3 (2.7–5.9) Tg CO2-eq yr−1 lower than, the total HFC emission estimates from the UK GHGI inventory. There are also significant discrepancies between the two estimates for the individual HFCs.
Wang, Mingyi ; Xiao, Mao ; Bertozzi, Barbara ; Marie, Guillaume ; Rörup, Birte ; Schulze, Benjamin ; Bardakov, Roman ; He, Xu-Cheng ; Shen, Jiali ; Scholz, Wiebke ; Marten, Ruby ; Dada, Lubna ; Baalbaki, Rima ; Lopez, Brandon ; Lamkaddam, Houssni ; Manninen, Hanna E. ; Amorim, Antonio ; Ataei, Farnoush ; Bogert, Pia ; Brasseur, Zoé ; Caudillo, Lucía ; De Menezes, Louis-Philippe ; Duplissy, Jonathan ; Ekman, Annica M. L. ; Finkenzeller, Henning ; Gonzalez Carracedo, Loïc ; Granzin, Manuel ; Guida, Roberto ; Heinritzi, Martin ; Hofbauer, Victoria ; Höhler, Kristina ; Korhonen, Kimmo ; Krechmer, Jordan E. ; Kürten, Christoph Andreas ; Lehtipalo, Katrianne ; Mahfouz, Naser G. A. ; Makhmutov, Vladimir ; Massabò, Dario ; Mathot, Serge ; Mauldin, Roy L. ; Mentler, Bernhard ; Müller, Tatjana ; Onnela, Antti ; Petäjä, Tuukka ; Philippov, Maxim ; Piedehierro, Ana A. ; Pozzer, Andrea ; Ranjithkumar, Ananth ; Schervish, Meredith ; Schobesberger, Siegfried ; Simon, Mario ; Stozhkov, Yuri ; Tomé, António ; Umo, Nsikanabasi Silas ; Vogel, Franziska ; Wagner, Robert ; Wang, Dongyu S. ; Weber, Stefan K. ; Welti, André ; Wu, Yusheng ; Zauner-Wieczorek, Marcel ; Sipilä, Mikko ; Winkler, Paul M. ; Hansel, Armin ; Baltensperger, Urs ; Kulmala, Markku ; Flagan, Richard C. ; Curtius, Joachim ; Riipinen, Ilona ; Gordon, Hamish ; Lelieveld, Jos ; El Haddad, Imad ; Volkamer, Rainer ; Worsnop, Douglas R. ; Christoudias, Theodoros ; Kirkby, Jasper ; Möhler, Ottmar ; Donahue, Neil McPherson
New particle formation in the upper free troposphere is a major global source of cloud condensation nuclei (CCN)1,2,3,4. However, the precursor vapours that drive the process are not well understood. With experiments performed under upper tropospheric conditions in the CERN CLOUD chamber, we show that nitric acid, sulfuric acid and ammonia form particles synergistically, at rates that are orders of magnitude faster than those from any two of the three components. The importance of this mechanism depends on the availability of ammonia, which was previously thought to be efficiently scavenged by cloud droplets during convection. However, surprisingly high concentrations of ammonia and ammonium nitrate have recently been observed in the upper troposphere over the Asian monsoon region5,6. Once particles have formed, co-condensation of ammonia and abundant nitric acid alone is sufficient to drive rapid growth to CCN sizes with only trace sulfate. Moreover, our measurements show that these CCN are also highly efficient ice nucleating particles—comparable to desert dust. Our model simulations confirm that ammonia is efficiently convected aloft during the Asian monsoon, driving rapid, multi-acid HNO3–H2SO4–NH3 nucleation in the upper troposphere and producing ice nucleating particles that spread across the mid-latitude Northern Hemisphere.
Kürten, Christoph Andreas ; Bergen, Anton ; Heinritzi, Martin ; Leiminger, Markus ; Lorenz, Verena ; Piel, Felix ; Simon, Mario ; Sitals, Robert ; Wagner, Andrea Christine ; Curtius, Joachim
The exact mechanisms for new particle formation (NPF) under different boundary layer conditions are not known yet. One important question is whether amines and sulfuric acid lead to efficient NPF in the atmosphere. Furthermore, it is not clear to what extent highly oxidized organic molecules (HOMs) are involved in NPF. We conducted field measurements at a rural site in central Germany in the proximity of three larger dairy farms to investigate whether there is a connection between NPF and the presence of amines and/or ammonia due to the local emissions from the farms. Comprehensive measurements using a nitrate chemical ionization–atmospheric pressure interface time-of-flight (CI-APi-TOF) mass spectrometer, a proton-transfer-reaction mass spectrometer (PTR-MS), particle counters and differential mobility analyzers (DMAs), as well as measurements of trace gases and meteorological parameters, were performed. We demonstrate here that the nitrate CI-APi-TOF is suitable for sensitive measurements of sulfuric acid, amines, a nitrosamine, ammonia, iodic acid and HOMs. NPF was found to correlate with sulfuric acid, while an anti-correlation with RH, amines and ammonia is observed. The anti-correlation between NPF and amines could be due to the efficient uptake of these compounds by nucleating clusters and small particles. Much higher HOM dimer (C19/C20 compounds) concentrations during the night than during the day indicate that these HOMs do not efficiently self-nucleate as no nighttime NPF is observed. Observed iodic acid probably originates from an iodine-containing reservoir substance, but the iodine signals are very likely too low to have a significant effect on NPF.
Kürten, Christoph Andreas ; Bergen, Anton ; Heinritzi, Martin ; Leiminger, Markus ; Lorenz, Verena ; Piel, Felix ; Simon, Mario ; Sitals, Robert ; Wagner, Andrea Christine ; Curtius, Joachim
The exact mechanisms for new particle formation (NPF) under different boundary layer conditions are not known yet. One important question is if amines and sulfuric acid lead to efficient NPF in the atmosphere. Furthermore, it is not clear to what extent highly oxidized organic molecules (HOM) are involved in NPF. We conducted field measurements at a rural site in central Germany in the proximity of three larger dairy farms to investigate if there is a connection between NPF and the presence of amines and/or ammonia due to the local emissions from the farms. Comprehensive measurements using a nitrate Chemical Ionization-Atmospheric Pressure interface-Time Of Flight (CI-APi-TOF) mass spectrometer, a Proton Transfer Reaction-Mass Spectrometer (PTR-MS), particle counters and Differential Mobility Analyzers (DMAs) as well as measurements of trace gases and meteorological parameters were performed. It is shown that the nitrate CI-APi-TOF is suitable for sensitive measurements of sulfuric acid, amines, a nitrosamine, ammonia, iodic acid and HOM. NPF was found to correlate with sulfuric acid, while an anti-correlation with RH, amines and ammonia is observed. The anti-correlation between NPF and amines could be due to the efficient uptake of these compounds by nucleating clusters and small particles. Much higher HOM dimer (C19/C20 compounds) concentrations during the night than during the day indicate that these HOM do not efficiently self-nucleate as no night-time NPF is observed. Observed iodic acid probably originates from an iodine-containing reservoir substance but the iodine signals are very likely too low to have a significant effect on NPF.
Heinritzi, Martin ; Simon, Mario ; Steiner, Gerhard ; Wagner, Andrea Christine ; Kürten, Christoph Andreas ; Hansel, Armin ; Curtius, Joachim
Knowledge about mass discrimination effects in a chemical ionization mass spectrometer (CIMS) is crucial for quantifying, e.g., the recently discovered extremely low volatile organic compounds (ELVOCs) and other compounds for which no calibration standard exists so far. Here, we present a simple way of estimating mass discrimination effects of a nitrate-based chemical ionization atmospheric pressure interface time-of-flight (CI-APi-TOF) mass spectrometer. Characterization of the mass discrimination is achieved by adding different perfluorinated acids to the mass spectrometer in amounts sufficient to deplete the primary ions significantly. The relative transmission efficiency can then be determined by comparing the decrease of signals from the primary ions and the increase of signals from the perfluorinated acids at higher masses. This method is in use already for PTR-MS; however, its application to a CI-APi-TOF brings additional difficulties, namely clustering and fragmentation of the measured compounds, which can be treated with statistical analysis of the measured data, leading to self-consistent results. We also compare this method to a transmission estimation obtained with a setup using an electrospray ion source, a high-resolution differential mobility analyzer and an electrometer, which estimates the transmission of the instrument without the CI source. Both methods give different transmission curves, indicating non-negligible mass discrimination effects of the CI source. The absolute transmission of the instrument without the CI source was estimated with the HR-DMA method to plateau between the m∕z range of 127 and 568 Th at around 1.5 %; however, for the CI source included, the depletion method showed a steady increase in relative transmission efficiency from the m∕z range of the primary ion (mainly at 62 Th) to around 550 Th by a factor of around 5. The main advantages of the depletion method are that the instrument is used in the same operation mode as during standard measurements and no knowledge of the absolute amount of the measured substance is necessary, which results in a simple setup.
Heinritzi, Martin ; Simon, Mario ; Steiner, Gerhard ; Wagner, Andrea Christine ; Kürten, Christoph Andreas ; Hansel, Armin ; Curtius, Joachim
Knowledge about mass discrimination effects in a chemical ionization mass spectrometer (CIMS) is crucial for quantifying, e.g., the recently discovered extremely low volatile organic compounds (ELVOCs) and other compounds for which no calibration standard exists so far. Here, we present a simple way of estimating mass discrimination effects of a nitrate-based chemical ionization atmospheric pressure interface time-of-flight (CI-APi-TOF) mass spectrometer. Characterization of the mass discrimination is achieved by adding different perfluorinated acids to the mass spectrometer in amounts sufficient to deplete the primary ions significantly. The relative transmission efficiency can then be determined by comparing the decrease of signals from the primary ions and the increase of signals from the perfluorinated acids at higher masses. This method is in use already for PTR-MS; however, its application to a CI-APi-TOF brings additional difficulties, namely clustering and fragmentation of the measured compounds, which can be treated with statistical analysis of the measured data, leading to selfconsistent results. We also compare this method to a transmission estimation obtained with a setup using an electrospray ion source, a high-resolution differential mobility analyzer and an electrometer, which estimates the transmission of the instrument without the CI source. Both methods give different transmission curves, indicating non-negligible mass discrimination effects of the CI source. The absolute transmission of the instrument without the CI source was estimated with the HR-DMA method to plateau between the m=z range of 127 and 568 Th at around 1.5 %; however, for the CI source included, the depletion method showed a steady increase in relative transmission efficiency from the m=z range of the primary ion (mainly at 62 Th) to around 550 Th by a factor of around 5. The main advantages of the depletion method are that the instrument is used in the same operation mode as during standard measurements and no knowledge of the absolute amount of the measured substance is necessary, which results in a simple setup.
Simon, Mario ; Heinritzi, Martin ; Herzog, Stephan ; Leiminger, Markus ; Bianchi, Federico ; Praplan, Arnaud Patrick ; Dommen, Josef ; Curtius, Joachim ; Kürten, Christoph Andreas
Amines are potentially important for atmospheric new particle formation, but their concentrations are usually low with typical mixing ratios in the pptv range or even smaller. Therefore, the demand for highly sensitive gas-phase amine measurements has emerged in the last several years. Nitrate chemical ionization mass spectrometry (CIMS) is routinely used for the measurement of gas-phase sulfuric acid in the sub-pptv range. Furthermore, extremely low volatile organic compounds (ELVOCs) can be detected with a nitrate CIMS. In this study we demonstrate that a nitrate CIMS can also be used for the sensitive measurement of dimethylamine (DMA, (CH3)2NH) using the NO3−•(HNO3)1 − 2• (DMA) cluster ion signal. Calibration measurements were made at the CLOUD chamber during two different measurement campaigns. Good linearity between 0 and ∼ 120 pptv of DMA as well as a sub-pptv detection limit of 0.7 pptv for a 10 min integration time are demonstrated at 278 K and 38 % RH.
Hall, Brad D. ; Engel, Andreas ; Mühle, Jens ; Elkins, James William ; Artuso, Florinda ; Atlas, Elliot L. ; Aydin, Murat ; Blake, Donald R. ; Brunke, Ernst-Günther ; Chiavarini, Salvatore ; Fraser, Paul J. ; Happell, James D. ; Krummel, Paul B. ; Levin, Ingeborg ; Loewenstein, Max ; Maione, Michela ; Montzka, Stephen A. ; O'Doherty, Simon ; Reimann, Stefan ; Rhoderick, George J. ; Saltzman, Eric S. ; Scheel, Hans-Eckhart ; Steele, L. Paul ; Vollmer, Martin K. ; Weiss, Ray F. ; Worthy, Douglas E. ; Yokouchi, Yoko
The International Halocarbons in Air Comparison Experiment (IHALACE) was conducted to document relationships between calibration scales among various laboratories that measure atmospheric greenhouse and ozone depleting gases. Six stainless steel cylinders containing natural and modified natural air samples were circulated among 19 laboratories. Results from this experiment reveal relatively good agreement among commonly used calibration scales for a number of trace gases present in the unpolluted atmosphere at pmol mol−1 (parts per trillion) levels, such as chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs), and hydrofluorocarbons (HFCs). Some scale relationships were found to be consistent with those derived from bi-lateral experiments or from analysis of atmospheric data, while others revealed discrepancies. The transfer of calibration scales among laboratories was found to be problematic in many cases, meaning that measurements tied to a common scale may not, in fact, be compatible. These results reveal substantial improvements in calibration over previous comparisons. However there is room for improvement in communication and coordination of calibration activities with respect to the measurement of halogenated and related trace gases.
Chirkov, Maksym ; Stiller, Gabriele ; Laeng, Alexandra ; Kellmann, Sylvia ; Clarmann, Thomas von ; Boone, Chris D. ; Elkins, James William ; Engel, Andreas ; Glatthor, Norbert ; Grabowski, Udo ; Harth, Christina M. ; Kiefer, Michael ; Kolonjari, Felicia ; Krummel, Paul B. ; Linden, Andrea ; Lunder, Chris Rene ; Miller, Benjamin R. ; Montzka, Stephen A. ; Mühle, Jens ; O'Doherty, Simon ; Orphal, Johannes ; Prinn, Ronald G. ; Toon, Geoffrey C. ; Vollmer, Martin K. ; Walker, Kaley A. ; Weiss, Ray F. ; Wiegele, Andreas ; Young, Dickon
We report on HCFC-22 data acquired by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) in the reduced spectral resolution nominal observation mode. The data cover the period from January 2005 to April 2012 and the altitude range from the upper troposphere (above cloud top altitude) to about 50 km. The profile retrieval was performed by constrained nonlinear least squares fitting of modelled spectra to the measured limb spectral radiances. The spectral ν4-band at 816.5 ± 13 cm−1 was used for the retrieval. A Tikhonov-type smoothing constraint was applied to stabilise the retrieval. In the lower stratosphere, we find a global volume mixing ratio of HCFC-22 of about 185 pptv in January 2005. The rate of linear growth in the lower latitudes lower stratosphere was about 6 to 7 pptv year−1 in the period 2005–2012. The profiles obtained were compared with ACE-FTS satellite data v3.5, as well as with MkIV balloon profiles and cryosampler balloon measurements. Between 13 and 22 km, average agreement within −3 to +5 pptv (MIPAS – ACE) with ACE-FTS v3.5 profiles is demonstrated. Agreement with MkIV solar occultation balloon-borne measurements is within 10–20 pptv below 30 km and worse above, while in situ cryosampler balloon measurements are systematically lower over their full altitude range by 15–50 pptv below 24 km and less than 10 pptv above 28 km. MIPAS HCFC-22 time series below 10 km altitude are shown to agree mostly well to corresponding time series of near-surface abundances from the NOAA/ESRL and AGAGE networks, although a more pronounced seasonal cycle is obvious in the satellite data. This is attributed to tropopause altitude fluctuations and subsidence of polar winter stratospheric air into the troposphere. A parametric model consisting of constant, linear, quasi-biennial oscillation (QBO) and several sine and cosine terms with different periods has been fitted to the temporal variation of stratospheric HCFC-22 for all 10°-latitude/1-to-2-km-altitude bins. The relative linear variation was always positive, with relative increases of 40–70 % decade−1 in the tropics and global lower stratosphere, and up to 120 % decade−1 in the upper stratosphere of the northern polar region and the southern extratropical hemisphere. Asian HCFC-22 emissions have become the major source of global upper tropospheric HCFC-22. In the upper troposphere, monsoon air, rich in HCFC-22, is instantaneously mixed into the tropics. In the middle stratosphere, between 20 and 30 km, the observed trend is inconsistent with the trend at the surface (corrected for the age of stratospheric air), hinting at circulation changes. There exists a stronger positive trend in HCFC-22 in the Southern Hemisphere and a more muted positive trend in the Northern Hemisphere, implying a potential change in the stratospheric circulation over the observation period.
Chirkov, Maksym ; Stiller, Gabriele ; Laeng, Alexandra ; Kellmann, Sylvia ; Clarmann, Thomas von ; Boone, Chris D. ; Elkins, James William ; Engel, Andreas ; Glatthor, Norbert ; Grabowski, Udo ; Harth, Christina M. ; Kiefer, Michael ; Kolonjari, Felicia ; Krummel, Paul B. ; Linden, Andrea ; Lunder, Chris Rene ; Miller, Benjamin R. ; Montzka, Stephen A. ; Mühle, Jens ; O'Doherty, Simon ; Orphal, Johannes ; Prinn, Ronald G. ; Toon, Geoffrey C. ; Vollmer, Martin K. ; Walker, Kaley A. ; Weiss, Ray F. ; Wiegele, Andreas ; Young, Dickon
We report on HCFC-22 data acquired by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) in reduced spectral resolution nominal mode in the period from January 2005 to April 2012 from version 5.02 level-1b spectral data and covering an altitude range from the upper troposphere (above cloud top altitude) to about 50 km. The profile retrieval was performed by constrained nonlinear least squares fitting of measured limb spectral radiances to modelled spectra. The spectral v4-band at 816.5 ± 13 cm-1 was used for the retrieval. A Tikhonov-type smoothing constraint was applied to stabilise the retrieval. In the lower stratosphere, we find a global volume mixing ratio of HCFC-22 of about 185 pptv in January 2005. The linear growth rate in the lower latitudes lower stratosphere was about 6 to 7 pptv yr-1 in the period 2005–2012. The obtained profiles were compared with ACE-FTS satellite data v3.5, as well as with MkIV balloon profiles and in situ cryosampler balloon measurements. Between 13 and 22 km, average agreement within -3 to +5 pptv (MIPAS–ACE) with ACE-FTS v3.5 pro files is demonstrated. Agreement with MkIV solar occultation balloon-borne measurements is within 10–20 pptv below 30 km and worse above, while in situ cryosampler balloon measurements are systematically lower over their full altitude range by 15– 50 pptv below 24 km and less than 10 pptv above 28 km. Obtained MIPAS HCFC-22 time series below 10 km altitude are shown to agree mostly well to corresponding time series of near-surface abundances from NOAA/ESRL and AGAGE networks, although a more pronounced seasonal cycle is obvious in the satellite data, probably due to tropopause altitude fluctuations and subsidence of polar winter stratospheric air into the troposphere. A parametric model consisting of constant, linear, quasi-biennial oscillation (QBO) and several sine and cosine terms with different periods has been fitted to the temporal variation of stratospheric HCFC-22 for all 10° latitude/1 to 2 km altitude bins. The relative linear variation was always positive, with relative increases of 40–70%decade-1 in the tropics and global lower stratosphere, and up to 120%decade-1 in the upper stratosphere of the northern polar region and the southern extratropical hemisphere. In the middle stratosphere between 20 and 30 km, the observed trend is not consistent with the age of stratospheric air-corrected trend at ground, but stronger positive at the Southern Hemisphere and less strong increasing in the Northern Hemisphere, hinting towards changes in the stratospheric circulation over the observation period.
Grünewald, Leon David ; Koch, Vitali ; Martin, Simon ; Yel, Ibrahim ; Eichler, Katrin ; Gruber-Rouh, Tatjana ; Lenga, Lukas Fabian ; Wichmann, Julian ; Alizadeh, Leona Soraja ; Albrecht, Moritz Hans Ernst ; Mader, Christoph ; Huizinga, Nicole A. ; D’Angelo, Tommaso ; Mazziotti, Silvio ; Wesarg, Stefan ; Vogl, Thomas J. ; Booz, Christian
Objectives: To evaluate the predictive value of volumetric bone mineral density (BMD) assessment of the lumbar spine derived from phantomless dual-energy CT (DECT)-based volumetric material decomposition as an indicator for the 2-year occurrence risk of osteoporosis-associated fractures. Methods: L1 of 92 patients (46 men, 46 women; mean age, 64 years, range, 19–103 years) who had undergone third-generation dual-source DECT between 01/2016 and 12/2018 was retrospectively analyzed. For phantomless BMD assessment, dedicated DECT postprocessing software using material decomposition was applied. Digital files of all patients were sighted for 2 years following DECT to obtain the incidence of osteoporotic fractures. Receiver operating characteristic (ROC) analysis was used to calculate cut-off values and logistic regression models were used to determine associations of BMD, sex, and age with the occurrence of osteoporotic fractures. Results: A DECT-derived BMD cut-off of 93.70 mg/cm3 yielded 85.45% sensitivity and 89.19% specificity for the prediction to sustain one or more osteoporosis-associated fractures within 2 years after BMD measurement. DECT-derived BMD was significantly associated with the occurrence of new fractures (odds ratio of 0.8710, 95% CI, 0.091–0.9375, p < .001), indicating a protective effect of increased DECT-derived BMD values. Overall AUC was 0.9373 (CI, 0.867–0.977, p < .001) for the differentiation of patients who sustained osteoporosis-associated fractures within 2 years of BMD assessment. Conclusions: Retrospective DECT-based volumetric BMD assessment can accurately predict the 2-year risk to sustain an osteoporosis-associated fracture in at-risk patients without requiring a calibration phantom. Lower DECT-based BMD values are strongly associated with an increased risk to sustain fragility fractures.
Key Points: Dual-energy CT–derived assessment of bone mineral density can identify patients at risk to sustain osteoporosis-associated fractures with a sensitivity of 85.45% and a specificity of 89.19%. The DECT-derived BMD threshold for identification of at-risk patients lies above the American College of Radiology (ACR) QCT guidelines for the identification of osteoporosis (93.70 mg/cm 3 vs 80 mg/cm 3 ).
Caudillo-Plath, Lucía ; Rörup, Birte ; Heinritzi, Martin ; Marie, Guillaume ; Simon, Mario ; Wagner, Andrea C. ; Müller, Tatjana ; Granzin, Manuel ; Amorim, António ; Ataei, Farnoush ; Baalbaki, Rima ; Bertozzi, Barbara ; Brasseur, Zoé ; Chiu, Randall ; Chu, Biwu ; Dada, Lubna ; Duplissy, Jonathan ; Finkenzeller, Henning ; Gonzalez Carracedo, Loïc ; He, Xu-Cheng ; Hofbauer, Victoria ; Kong, Weimeng ; Lamkaddam, Houssni ; Lee, Chuan P. ; Lopez, Brandon ; Mahfouz, Naser G. A. ; Makhmutov, Vladimir ; Manninen, Hanna E. ; Marten, Ruby ; Massabò, Dario ; Mauldin, Roy L. ; Mentler, Bernhard ; Molteni, Ugo ; Onnela, Antti ; Pfeifer, Joschka ; Philippov, Maxim ; Piedehierro, Ana A. ; Schervish, Meredith ; Scholz, Wiebke ; Schulze, Benjamin ; Shen, Jiali ; Stolzenburg, Dominik ; Stožkov, Ju. I. ; Surdu, Mihnea ; Tauber, Christian ; Tham, Yee Jun ; Tian, Ping ; Tomé, António ; Vogt, Steffen ; Wang, Mingyi ; Wang, Dongyu S. ; Weber, Stefan K. ; Welti, André ; Yonghong, Wang ; Yusheng, Wu ; Zauner-Wieczorek, Marcel ; Baltensperger, Urs ; El Haddad, Imad ; Flagan, Richard C. ; Hansel, Armin ; Höhler, Kristina ; Kirkby, Jasper ; Kulmala, Markku ; Lehtipalo, Katrianne ; Möhler, Ottmar ; Saathoff, Harald ; Volkamer, Rainer ; Winkler, Paul M. ; Donahue, Neil M. ; Kürten, Christoph Andreas ; Curtius, Joachim
Biogenic organic precursors play an important role in atmospheric new particle formation (NPF). One of the major precursor species is α-pinene, which upon oxidation can form a suite of products covering a wide range of volatilities. Highly oxygenated organic molecules (HOMs) comprise a fraction of the oxidation products formed. While it is known that HOMs contribute to secondary organic aerosol (SOA) formation, including NPF, they have not been well studied in newly formed particles due to their very low mass concentrations. Here we present gas- and particle-phase chemical composition data from experimental studies of α-pinene oxidation, including in the presence of isoprene, at temperatures (−50 and −30 ∘C) and relative humidities (20 % and 60 %) relevant in the upper free troposphere. The measurements took place at the CERN Cosmics Leaving Outdoor Droplets (CLOUD) chamber. The particle chemical composition was analyzed by a thermal desorption differential mobility analyzer (TD-DMA) coupled to a nitrate chemical ionization–atmospheric pressure interface–time-of-flight (CI-APi-TOF) mass spectrometer. CI-APi-TOF was used for particle- and gas-phase measurements, applying the same ionization and detection scheme. Our measurements revealed the presence of C8−10 monomers and C18−20 dimers as the major compounds in the particles (diameter up to ∼ 100 nm). Particularly, for the system with isoprene added, C5 (C5H10O5−7) and C15 compounds (C15H24O5−10) were detected. This observation is consistent with the previously observed formation of such compounds in the gas phase. However, although the C5 and C15 compounds do not easily nucleate, our measurements indicate that they can still contribute to the particle growth at free tropospheric conditions. For the experiments reported here, most likely isoprene oxidation products enhance the growth of particles larger than 15 nm. Additionally, we report on the nucleation rates measured at 1.7 nm (J1.7 nm) and compared with previous studies, we found lower J1.7 nm values, very likely due to the higher α-pinene and ozone mixing ratios used in the present study.
Caudillo-Plath, Lucı́a ; Rörup, Birte ; Heinritzi, Martin ; Marie, Guillaume ; Simon, Mario ; Wagner, Andrea C. ; Müller, Tatjana ; Granzin, Manuel ; Amorim, Antonio ; Ataei, Farnoush ; Baalbaki, Rima ; Bertozzi, Barbara ; Brasseur, Zoé ; Chiu, Randall ; Chu, Biwu ; Dada, Lubna ; Duplissy, Jonathan ; Finkenzeller, Henning ; Gonzalez Carracedo, Loïc ; He, Xu-Cheng ; Hofbauer, Victoria ; Kong, Weimeng ; Lamkaddam, Houssni ; Lee, Chuan P ; Lopez, Brandon ; Mahfouz, Naser G. A. ; Makhmutov, Vladimir ; Manninen, Hanna E. ; Marten, Ruby ; Massabò, Dario ; Mauldin, Roy L. ; Mentler, Bernhard ; Molteni, Ugo ; Onnela, Antti ; Pfeifer, Joschka ; Philippov, Maxim ; Piedehierro, Ana A. ; Schervish, Meredith ; Scholz, Wiebke ; Schulze, Benjamin ; Shen, Jiali ; Stolzenburg, Dominik ; Stožkov, Ju. I. ; Surdu, Mihnea ; Tauber, Christian ; Tham, Yee Jun ; Tian, Ping ; Tomé, António ; Vogt, Steffen ; Wang, Mingyi ; Wang, Dongyu S. ; Weber, Stefan K. ; Welti, André ; Yonghong, Wang ; Yusheng, Wu ; Zauner-Wieczorek, Marcel ; Baltensperger, Urs ; El Haddad, Imad ; Flagan, Richard C. ; Hansel, Armin ; Höhler, Kristina ; Kirkby, Jasper ; Kulmala, Markku ; Lehtipalo, Katrianne ; Möhler, Ottmar ; Saathoff, Harald ; Volkamer, Rainer ; Winkler, Paul M. ; Donahue, Neil M. ; Kürten, Christoph Andreas ; Curtius, Joachim
Biogenic organic precursors play an important role in atmospheric new particle formation (NPF). One of the major precursor species is α-pinene, which upon oxidation can form a suite of products covering a wide range of volatilities. Highly oxygenated organic molecules (HOMs) comprise a fraction of the oxidation products formed. While it is known that HOMs contribute to secondary organic aerosol (SOA) formation, including NPF, they have not been well studied in newly formed particles due to their very low mass concentrations. Here we present gas- and particle-phase chemical composition data from experimental studies of α-pinene oxidation, including in the presence of isoprene, at temperatures (−50 and −30 ∘C) and relative humidities (20 % and 60 %) relevant in the upper free troposphere. The measurements took place at the CERN Cosmics Leaving Outdoor Droplets (CLOUD) chamber. The particle chemical composition was analyzed by a thermal desorption differential mobility analyzer (TD-DMA) coupled to a nitrate chemical ionization–atmospheric pressure interface–time-of-flight (CI-APi-TOF) mass spectrometer. CI-APi-TOF was used for particle- and gas-phase measurements, applying the same ionization and detection scheme. Our measurements revealed the presence of C8−10 monomers and C18−20 dimers as the major compounds in the particles (diameter up to ∼ 100 nm). Particularly, for the system with isoprene added, C5 (C5H10O5−7) and C15 compounds (C15H24O5−10) were detected. This observation is consistent with the previously observed formation of such compounds in the gas phase. However, although the C5 and C15 compounds do not easily nucleate, our measurements indicate that they can still contribute to the particle growth at free tropospheric conditions. For the experiments reported here, most likely isoprene oxidation products enhance the growth of particles larger than 15 nm. Additionally, we report on the nucleation rates measured at 1.7 nm (J1.7 nm) and compared with previous studies, we found lower J1.7 nm values, very likely due to the higher α-pinene and ozone mixing ratios used in the present study.
Wagner, Andrea Christine ; Bergen, Anton ; Brilke, Sophia ; Fuchs, Claudia ; Ernst, Markus ; Hoker, Jesica ; Heinritzi, Martin ; Simon, Mario ; Bühner, Bertram ; Curtius, Joachim ; Kürten, Christoph Andreas
A new method for size-resolved chemical analysis of nucleation mode aerosol particles (size range from ∼10 to ∼30 nm) is presented. The Thermal Desorption Differential Mobility Analyzer (TD-DMA) uses an online, discontinuous principle. The particles are charged, a specific size is selected by differential mobility analysis and they are collected on a filament by electrostatic precipitation. Subsequently, the sampled mass is evaporated in a clean carrier gas and analyzed by a chemical ionization mass spectrometer. Gas-phase measurements are performed with the same mass spectrometer during the sampling of particles. The characterization shows reproducible results, with a particle size resolution of 1.19 and the transmission efficiency for 15 nm particles being slightly above 50 %. The signal from the evaporation of a test substance can be detected starting from 0.01 ng and shows a linear response in the mass spectrometer. Instrument operation in the range of pg m−3 is demonstrated by an example measurement of 15 nm particles produced by nucleation from dimethylamine, sulfuric acid and water.
Wagner, Andrea Christine ; Bergen, Anton ; Brilke, Sophia ; Fuchs, Claudia ; Ernst, Markus ; Hoker, Jesica ; Heinritzi, Martin ; Simon, Mario ; Bühner, Bertram ; Curtius, Joachim ; Kürten, Christoph Andreas
A new method for size resolved chemical analysis of nucleation mode aerosol particles (size range from ~10 to ~30 nm) is presented. The Thermal Desorption Differential Mobility Analyzer (TD-DMA) uses an online, discontinuous principle. The particles are charged, a specific size is selected by differential mobility analysis and they are collected on a filament by electrostatic precipitation. Subsequently, the sampled mass is evaporated in a clean carrier gas and analyzed by a chemical ionization mass spectrometer. Gas phase measurements are performed with the same mass spectrometer during the sampling of particles. The characterization shows reproducible results, with a particle size resolution of 1.19 and the transmission efficiency for 15 nm particles being slightly above 50 %. The signal from the evaporation of a test substance can be detected starting from 0.01 ng and shows a linear response in the mass spectrometer. Instrument operation in the range of pg/m3 is demonstrated by an example measurement of 15 nm particles produced by nucleation from dimethylamine, sulfuric acid and water.
Simon, Mario ; Heinritzi, Martin ; Herzog, Stephan ; Leiminger, Markus ; Bianchi, Federico ; Praplan, Arnaud Patrick ; Dommen, Josef ; Curtius, Joachim ; Kürten, Christoph Andreas
Amines are potentially important for atmospheric new particle formation, but their concentrations are usually low with typical mixing ratios in the pptv range or even smaller. Therefore, the demand for highly sensitive gas-phase amine measurements has emerged in the last several years. Nitrate chemical ionization mass spectrometry (CIMS) is routinely used for the measurement of gasphase sulfuric acid in the sub-pptv range. Furthermore, extremely low volatile organic compounds (ELVOCs) can be detected with a nitrate CIMS. In this study we demonstrate that a nitrate CIMS can also be used for the sensitive measurement of dimethylamine (DMA, (CH3/2NH) using the NO3−•(HNO3)1 − 2• (DMA) cluster ion signal. Calibration measurements were made at the CLOUD chamber during two different measurement campaigns. Good linearity between 0 and ~120 pptv of DMA as well as a sub-pptv detection limit of 0.7 pptv for a 10 min integration time are demonstrated at 278K and 38% RH.
Alizadeh, Leona Soraja ; Koch, Vitali ; Yel, Ibrahim ; Grünewald, Leon David ; Mathies, Daniel ; Martin, Simon ; Vogl, Thomas J. ; Rauschning, Dominic ; Booz, Christian
Vaccination represents one of the fundamentals in the fight against SARS-CoV-2. Myocarditis has been reported as a rare but possible adverse consequence of different vaccines, and its clinical presentation can range from mild symptoms to acute heart failure. We report a case of a 29-year-old man who presented with fever and retrosternal pain after receiving SARS-CoV-2 vaccine. Cardiac magnetic resonance imaging and laboratory data revealed typical findings of acute myocarditis.
Koch, Vitali ; Albrecht, Moritz Hans Ernst ; Grünewald, Leon David ; Yel, Ibrahim ; Eichler, Katrin ; Gruber-Rouh, Tatjana ; Hammerstingl, Renate Maria ; Burck, Iris ; Wichmann, Julian ; Alizadeh, Leona Soraja ; Vogl, Thomas J. ; Lenga, Lukas ; Mader, Christoph ; Martin, Simon ; Mazziotti, Silvio ; D’Angelo, Tommaso ; Booz, Christian
Objectives: To investigate the diagnostic accuracy of color-coded contrast-enhanced dual-energy CT virtual noncalcium (VNCa) reconstructions for the assessment of lumbar disk herniation compared to unenhanced VNCa imaging.
Methods: A total of 91 patients were retrospectively evaluated (65 years ± 16; 43 women) who had undergone third-generation dual-source dual-energy CT and 3.0-T MRI within an examination interval up to 3 weeks between November 2019 and December 2020. Eight weeks after assessing unenhanced color-coded VNCa reconstructions for the presence and degree of lumbar disk herniation, corresponding contrast-enhanced portal venous phase color-coded VNCa reconstructions were independently analyzed by the same five radiologists. MRI series were additionally analyzed by one highly experienced musculoskeletal radiologist and served as reference standard.
Results: MRI depicted 210 herniated lumbar disks in 91 patients. VNCa reconstructions derived from contrast-enhanced CT scans showed similar high overall sensitivity (93% vs 95%), specificity (94% vs 95%), and accuracy (94% vs 95%) for the assessment of lumbar disk herniation compared to unenhanced VNCa images (all p > .05). Interrater agreement in VNCa imaging was excellent for both, unenhanced and contrast-enhanced CT (κ = 0.84 vs κ = 0.86; p > .05). Moreover, ratings for diagnostic confidence, image quality, and noise differed not significantly between unenhanced and contrast-enhanced VNCa series (all p > .05).
Conclusions: Color-coded VNCa reconstructions derived from contrast-enhanced dual-energy CT yield similar diagnostic accuracy for the depiction of lumbar disk herniation compared to unenhanced VNCa imaging and therefore may improve opportunistic retrospective lumbar disk herniation assessment, particularly in case of staging CT examinations.
Key Points
• Color-coded dual-source dual-energy CT virtual noncalcium (VNCa) reconstructions derived from portal venous phase yield similar high diagnostic accuracy for the assessment of lumbar disk herniation compared to unenhanced VNCa CT series (94% vs 95%) with MRI serving as a standard of reference.
• Diagnostic confidence, image quality, and noise levels differ not significantly between unenhanced and contrast-enhanced portal venous phase VNCa dual-energy CT series.
• Dual-source dual-energy CT might have the potential to improve opportunistic retrospective lumbar disk herniation assessment in CT examinations performed for other indications through reconstruction of VNCa images.
Blum, Andrea ; Khalifa, Saleem ; Nordström, Karl ; Simon, Martin ; Schulz, Marcel Holger ; Schmit, Manfred J.
KDEL receptors (KDELRs) represent transmembrane proteins of the secretory pathway which regulate the retention of soluble ER-residents as well as retrograde and anterograde vesicle trafficking. In addition, KDELRs are involved in the regulation of cellular stress response and ECM degradation. For a deeper insight into KDELR1 specific functions, we characterised a KDELR1-KO cell line (HAP1) through whole transcriptome analysis by comparing KDELR1-KO cells with its respective HAP1 wild-type. Our data indicate more than 300 significantly and differentially expressed genes whose gene products are mainly involved in developmental processes such as cell adhesion and ECM composition, pointing out to severe cellular disorders due to a loss of KDELR1. Impaired adhesion capacity of KDELR1-KO cells was further demonstrated through in vitro adhesion assays, while collagen- and/or laminin-coating nearly doubled the adhesion property of KDELR1-KO cells compared to wild-type, confirming a transcriptional adaptation to improve or restore the cellular adhesion capability. Perturbations within the secretory pathway were verified by an increased secretion of ER-resident PDI and decreased cell viability under ER stress conditions, suggesting KDELR1-KO cells to be severely impaired in maintaining cellular homeostasis.
Wenzel, Mike ; Preißer, Felix Martin ; Mueller, Matthias ; Theißen, Lena Hermine ; Welte, Maria-Noemi ; Höh, Robert Benedikt ; Humke, Clara Julia ; Bernatz, Simon ; Bodelle, Boris ; Würnschimmel, Christoph ; Tilki, Derya ; Huland, Hartwig ; Graefen, Markus ; Roos, Frederik ; Becker, Andreas ; Karakiewicz, Pierre I. ; Chun, Felix ; Kluth, Luis ; Mandel, Philipp
Purpose: To test the effect of anatomic variants of the prostatic apex overlapping the membranous urethra (Lee type classification), as well as median urethral sphincter length (USL) in preoperative multiparametric magnetic resonance imaging (mpMRI) on the very early continence in open (ORP) and robotic-assisted radical prostatectomy (RARP) patients. Methods: In 128 consecutive patients (01/2018–12/2019), USL and the prostatic apex classified according to Lee types A–D in mpMRI prior to ORP or RARP were retrospectively analyzed. Uni- and multivariable logistic regression models were used to identify anatomic characteristics for very early continence rates, defined as urine loss of ≤ 1 g in the PAD-test. Results: Of 128 patients with mpMRI prior to surgery, 76 (59.4%) underwent RARP vs. 52 (40.6%) ORP. In total, median USL was 15, 15 and 10 mm in the sagittal, coronal and axial dimensions. After stratification according to very early continence in the PAD-test (≤ 1 g vs. > 1 g), continent patients had significantly more frequently Lee type D (71.4 vs. 54.4%) and C (14.3 vs. 7.6%, p = 0.03). In multivariable logistic regression models, the sagittal median USL (odds ratio [OR] 1.03) and Lee type C (OR: 7.0) and D (OR: 4.9) were independent predictors for achieving very early continence in the PAD-test. Conclusion: Patients’ individual anatomical characteristics in mpMRI prior to radical prostatectomy can be used to predict very early continence. Lee type C and D suggest being the most favorable anatomical characteristics. Moreover, longer sagittal median USL in mpMRI seems to improve very early continence rates.
Simon, Thorsten ; Hero, Barbara ; Faldum, Andreas ; Handgretinger, Rupert ; Schrappe, Martin ; Klingebiel, Thomas ; Berthold, Frank
Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.
In the life sciences, there is an ongoing discussion about a perceived ‘reproducibility crisis’. However, it remains unclear to which extent the perceived lack of reproducibility is the consequence of issues that can be tackled and to which extent it may be the consequence of unrealistic expectations of the technical level of reproducibility. Large-scale, multi-institutional experimental replication studies are very cost- and time-intensive. This Perspective suggests an alternative, complementary approach: meta-research using sociological and philosophical methodologies to examine researcher trust in data. An improved understanding of the criteria used by researchers to judge data reliability will provide crucial, initial evidence on the actual scale of the reproducibility crisis and on measures to tackle it.
Hygroscopicity of nanoparticles produced from homogeneous
nucleation in the CLOUD experiments
(2016)
Kim, Jaeseok ; Ahlm, Lars ; Yli-Juuti, Taina ; Lawler, Michael Joseph ; Keskinen, Helmi ; Tröstl, Jasmin ; Schobesberger, Siegfried ; Duplissy, Jonathan ; Amorim, Antonio ; Bianchi, Federico ; Donahue, Neil McPherson ; Flagan, Richard C. ; Hakala, Jani ; Heinritzi, Martin ; Jokinen, Tuija ; Kürten, Christoph Andreas ; Laaksonen, Ari ; Lehtipalo, Katrianne ; Miettinen, Pasi ; Petäjä, Tuukka ; Rissanen, Matti P. ; Rondo, Linda ; Sengupta, Kamalika ; Simon, Mario ; Tomé, Antonio ; Williamson, Christina ; Wimmer, Daniela ; Winkler, Paul M. ; Ehrhart, Sebastian ; Ye, Penglin ; Kirkby, Jasper ; Curtius, Joachim ; Baltensperger, Urs ; Kulmala, Markku ; Lehtinen, Kari E. J. ; Smith, James N. ; Riipinen, Ilona ; Virtanen, Annele
Sulfuric acid, amines and oxidized organics have been found to be important compounds in the nucleation and initial growth of atmospheric particles. Because of the challenges involved in determining the chemical composition of objects with very small mass, however, the properties of the freshly nucleated particles and the detailed pathways of their formation processes are still not clear. In this study, we focus on a challenging size range, i.e., particles that have grown to diameters of 10 and 15 nm following nucleation, and measure their water uptake. Water uptake is useful information for indirectly obtaining chemical composition of aerosol particles. We use a nanometer-hygroscopicity tandem differential mobility analyzer (nano-HTDMA) at subsaturated conditions (ca. 90 % relative humidity at 293 K) to measure the hygroscopicity of particles during the seventh Cosmics Leaving OUtdoor Droplets (CLOUD7) campaign performed at CERN in 2012. In CLOUD7, the hygroscopicity of nucleated nanoparticles was measured in the presence of sulfuric acid, sulfuric acid–dimethylamine, and sulfuric acid–organics derived from α-pinene oxidation. The hygroscopicity parameter κ decreased with increasing particle size, indicating decreasing acidity of particles. No clear effect of the sulfuric acid concentration on the hygroscopicity of 10 nm particles produced from sulfuric acid and dimethylamine was observed, whereas the hygroscopicity of 15 nm particles sharply decreased with decreasing sulfuric acid concentrations. In particular, when the concentration of sulfuric acid was 5.1 × 106 molecules cm−3 in the gas phase, and the dimethylamine mixing ratio was 11.8 ppt, the measured κ of 15 nm particles was 0.31 ± 0.01: close to the value reported for dimethylaminium sulfate (DMAS) (κDMAS ∼ 0.28). Furthermore, the difference in κ between sulfuric acid and sulfuric acid–imethylamine experiments increased with increasing particle size. The κ values of particles in the presence of sulfuric acid and organics were much smaller than those of particles in the presence of sulfuric acid and dimethylamine. This suggests that the organics produced from α-pinene ozonolysis play a significant role in particle growth even at 10 nm sizes.
Hygroscopicity of nanoparticles produced from homogeneous nucleation in the CLOUD experiments
(2015)
Kim, Jaeseok ; Ahlm, Lars ; Yli-Juuti, Taina ; Lawler, Michael Joseph ; Keskinen, Helmi ; Tröstl, Jasmin ; Schobesberger, Siegfried ; Duplissy, Jonathan ; Amorim, Antonio ; Bianchi, Federico ; Donahue, Neil McPherson ; Flagan, Richard C. ; Hakala, Jani ; Heinritzi, Martin ; Jokinen, Tuija ; Kürten, Christoph Andreas ; Laaksonen, Ari ; Lehtipalo, Katrianne ; Miettinen, Pasi ; Petäjä, Tuukka ; Rissanen, Matti P. ; Rondo, Linda ; Sengupta, Kamalika ; Simon, Mario ; Tomé, Antonio ; Williamson, Christina ; Wimmer, Daniela ; Winkler, Paul M. ; Ehrhart, Sebastian ; Ye, Penglin ; Kirkby, Jasper ; Curtius, Joachim ; Kulmala, Markku ; Lehtinen, Kari E. J. ; Smith, James N. ; Riipinen, Ilona ; Virtanen, Annele
Sulfuric acid, amines and oxidized organics have been found to be important compounds in the nucleation and initial growth of atmospheric particles. Because of the challenges involved in determining the chemical composition of objects with very small mass, however, the properties of the freshly nucleated particles and the detailed pathways of their formation processes are still not clear. In this study, we focus on a challenging size range, i.e. particles that have grown to diameters of 10 and 15nm following nucleation, and measure their water uptake. Water uptake constrains their chemical composition. We use a nanometer-hygroscopicity tandem differential mobility analyzer (nano-HTDMA) at subsaturated conditions (ca. 90% relative humidity at 293 K) to measure the hygroscopicity of particles during the seventh Cosmics Leaving OUtdoor Droplets (CLOUD7) experiments performed at CERN in 2012. In CLOUD7, the hygroscopicity of nucleated nanoparticles was measured in the presence of sulfuric acid, sulfuric acid-dimethylamine, and sulfuric acid-organics derived from α-pinene oxidation. The hygroscopicity parameter Κ decreased with increasing particle size indicating decreasing acidity of particles. No clear effect of the sulfuric acid monomer concentrations on the hygroscopicities of 10nm particles produced from sulfuric acid and dimethylamine was observed, whereas the hygroscopicity of 15nm particles sharply decreased with decreasing sulfuric acid monomer concentrations. In 20 particular, when the concentrations of sulfuric acid was 5.1 x 106 molecules cm exp -3 in the gas phase, and the dimethylamine mixing ratio was 11.8 ppt, the measured Κ of 15nm particles was 0.3 ± 0.01 close to the value reported for dimethylamine sulfate (DMAS) (Κ DMAS ~ 0.28). Furthermore, the difference in Κ between sulfuric acid and sulfuric acid-dimethylamine experiments increased with increasing particle size. The Κ values of particles in the presence of sulfuric acid and organics were much smaller than those of particles in the presence of sulfuric acid and dimethylamine. This suggests that the organics produced from α-pinene ozonolysis play a significant role in particle growth already at 10nm sizes.
Vockert, Marco ; Weber, Günter ; Bräuning, Harald ; Surzhykov, Andrey ; Brandau, Carsten ; Fritzsche, Stephan ; Geyer, Simon ; Hagmann, Siegbert ; Heß, Sebastian ; Kozhuharov, Christophor ; Märtin, Renate ; Petridis, Nikolaos ; Heß, Regina ; Trotsenko, Sergiy ; Litvinov, Yuri A. ; Glorius, Jan ; Gumberidze, Alexandre ; Steck, Markus ; Litvinov, Sergey A. ; Gaßner, Tobias ; Hillenbrand, Pierre-Michel ; Lestinsky, Michael ; Nolden, Fritz ; Sanjari, Mohammad Shahab ; Popp, Ulrich ; Trageser, Christian ; Winters, Danyal Ferdinant Alexander ; Spillmann, Uwe ; Krings, Thomas ; Stöhlker, Thomas
The radiative electron capture (REC) into the K shell of bare Xe ions colliding with a hydrogen gas target has been investigated. In this study, the degree of linear polarization of the K-REC radiation was measured and compared with rigorous relativistic calculations as well as with the previous results recorded for U92+. Owing to the improved detector technology, a significant gain in precision of the present polarization measurement is achieved compared to the previously published results. The obtained data confirms that for medium-Z ions such as Xe, the REC process is a source of highly polarized x rays which can easily be tuned with respect to the degree of linear polarization and the photon energy. We argue, in particular, that for relatively low energies the photons emitted under large angles are almost fully linear polarized.
D’Angelo, Tommaso ; Albrecht, Moritz Hans Ernst ; Caudo, Danilo ; Mazziotti, Silvio ; Vogl, Thomas J. ; Wichmann, Julian ; Martin, Simon ; Yel, Ibrahim ; Ascenti, Giorgio ; Koch, Vitali ; Cicero, Giuseppe ; Blandino, Alfredo ; Booz, Christian
Dual-energy CT (DECT) has emerged into clinical routine as an imaging technique with unique postprocessing utilities that improve the evaluation of different body areas. The virtual non-calcium (VNCa) reconstruction algorithm has shown beneficial effects on the depiction of bone marrow pathologies such as bone marrow edema. Its main advantage is the ability to substantially increase the image contrast of structures that are usually covered with calcium mineral, such as calcified vessels or bone marrow, and to depict a large number of traumatic, inflammatory, infiltrative, and degenerative disorders affecting either the spine or the appendicular skeleton. Therefore, VNCa imaging represents another step forward for DECT to image conditions and disorders that usually require the use of more expensive and time-consuming techniques such as magnetic resonance imaging, positron emission tomography/CT, or bone scintigraphy. The aim of this review article is to explain the technical background of VNCa imaging, showcase its applicability in the different body regions, and provide an updated outlook on the clinical impact of this technique, which goes beyond the sole improvement in image quality.
Koch, Vitali ; Yel, Ibrahim ; Grünewald, Leon David ; Beckers, Sebastian ; Burck, Iris ; Lenga, Lukas Fabian ; Martin, Simon S. ; Mader, Christoph ; Wichmann, Julian ; Albrecht, Moritz Hans Ernst ; Eichler, Katrin ; Gruber-Rouh, Tatjana ; D’Angelo, Tommaso ; Mazziotti, Silvio ; Ascenti, Giorgio ; Vogl, Thomas J. ; Booz, Christian
Objectives: To determine the diagnostic accuracy of dual-energy CT (DECT) virtual noncalcium (VNCa) reconstructions for assessing thoracic disk herniation compared to standard grayscale CT. Methods: In this retrospective study, 87 patients (1131 intervertebral disks; mean age, 66 years; 47 women) who underwent third-generation dual-source DECT and 3.0-T MRI within 3 weeks between November 2016 and April 2020 were included. Five blinded radiologists analyzed standard DECT and color-coded VNCa images after a time interval of 8 weeks for the presence and degree of thoracic disk herniation and spinal nerve root impingement. Consensus reading of independently evaluated MRI series served as the reference standard, assessed by two separate experienced readers. Additionally, image ratings were carried out by using 5-point Likert scales. Results: MRI revealed a total of 133 herniated thoracic disks. Color-coded VNCa images yielded higher overall sensitivity (624/665 [94%; 95% CI, 0.89–0.96] vs 485/665 [73%; 95% CI, 0.67–0.80]), specificity (4775/4990 [96%; 95% CI, 0.90–0.98] vs 4066/4990 [82%; 95% CI, 0.79–0.84]), and accuracy (5399/5655 [96%; 95% CI, 0.93–0.98] vs 4551/5655 [81%; 95% CI, 0.74–0.86]) for the assessment of thoracic disk herniation compared to standard CT (all p < .001). Interrater agreement was excellent for VNCa and fair for standard CT (ϰ = 0.82 vs 0.37; p < .001). In addition, VNCa imaging achieved higher scores regarding diagnostic confidence, image quality, and noise compared to standard CT (all p < .001). Conclusions: Color-coded VNCa imaging yielded substantially higher diagnostic accuracy and confidence for assessing thoracic disk herniation compared to standard CT.
Koch, Vitali ; Große Hokamp, Nils ; Albrecht, Moritz Hans Ernst ; Grünewald, Leon David ; Yel, Ibrahim ; Borggrefe, Jan ; Wesarg, Stefan ; Eichler, Katrin ; Burck, Iris ; Gruber-Rouh, Tatjana ; Lenga, Lukas Fabian ; Vogl, Thomas J. ; Martin, Simon ; Wichmann, Julian ; Hammerstingl, Renate Maria ; Alizadeh, Leona Soraja ; Mader, Christoph ; Huizinga, Nicole A. ; D’Angelo, Tommaso ; Ascenti, Giorgio ; Mazziotti, Silvio ; Booz, Christian
Background: Dual-source dual-energy computed tomography (DECT) offers the potential for opportunistic osteoporosis screening by enabling phantomless bone mineral density (BMD) quantification. This study sought to assess the accuracy and precision of volumetric BMD measurement using dual-source DECT in comparison to quantitative CT (QCT). Methods: A validated spine phantom consisting of three lumbar vertebra equivalents with 50 (L1), 100 (L2), and 200 mg/cm3 (L3) calcium hydroxyapatite (HA) concentrations was scanned employing third-generation dual-source DECT and QCT. While BMD assessment based on QCT required an additional standardised bone density calibration phantom, the DECT technique operated by using a dedicated postprocessing software based on material decomposition without requiring calibration phantoms. Accuracy and precision of both modalities were compared by calculating measurement errors. In addition, correlation and agreement analyses were performed using Pearson correlation, linear regression, and Bland-Altman plots. Results: DECT-derived BMD values differed significantly from those obtained by QCT (p < 0.001) and were found to be closer to true HA concentrations. Relative measurement errors were significantly smaller for DECT in comparison to QCT (L1, 0.94% versus 9.68%; L2, 0.28% versus 5.74%; L3, 0.24% versus 3.67%, respectively). DECT demonstrated better BMD measurement repeatability compared to QCT (coefficient of variance < 4.29% for DECT, < 6.74% for QCT). Both methods correlated well to each other (r = 0.9993; 95% confidence interval 0.9984–0.9997; p < 0.001) and revealed substantial agreement in Bland-Altman plots. Conclusions: Phantomless dual-source DECT-based BMD assessment of lumbar vertebra equivalents using material decomposition showed higher diagnostic accuracy compared to QCT.
Cavallaro, Marco ; D’Angelo, Tommaso ; Albrecht, Moritz Hans Ernst ; Yel, Ibrahim ; Martin, Simon S. ; Wichmann, Julian ; Lenga, Lukas Fabian ; Mazziotti, Silvio ; Blandino, Alfredo ; Ascenti, Giorgio ; Longo, Marcello ; Vogl, Thomas J. ; Booz, Christian
Objectives: To compare dual-energy CT (DECT) and MRI for assessing presence and extent of traumatic bone marrow edema (BME) and fracture line depiction in acute vertebral fractures. Methods: Eighty-eight consecutive patients who underwent dual-source DECT and 3-T MRI of the spine were retrospectively analyzed. Five radiologists assessed all vertebrae for presence and extent of BME and for identification of acute fracture lines on MRI and, after 12 weeks, on DECT series. Additionally, image quality, image noise, and diagnostic confidence for overall diagnosis of acute vertebral fracture were assessed. Quantitative analysis of CT numbers was performed by a sixth radiologist. Two radiologists analyzed MRI and grayscale DECT series to define the reference standard. Results: For assessing BME presence and extent, DECT showed high sensitivity (89% and 84%, respectively) and specificity (98% in both), and similarly high diagnostic confidence compared to MRI (2.30 vs. 2.32; range 0–3) for the detection of BME (p = .72). For evaluating acute fracture lines, MRI achieved high specificity (95%), moderate sensitivity (76%), and a significantly lower diagnostic confidence compared to DECT (2.42 vs. 2.62, range 0–3) (p < .001). A cutoff value of − 0.43 HU provided a sensitivity of 89% and a specificity of 90% for diagnosing BME, with an overall AUC of 0.96. Conclusions: DECT and MRI provide high diagnostic confidence and image quality for assessing acute vertebral fractures. While DECT achieved high overall diagnostic accuracy in the analysis of BME presence and extent, MRI provided moderate sensitivity and lower confidence for evaluating fracture lines.
Praktiknjo, Michael ; Simón-Talero, Macarena ; Römer, Julia ; Roccarina, Davide ; Martínez, Javier ; Lampichler, Katharina ; Baiges, Anna ; Low, Gavin ; Llop, Elba ; Maurer, Martin H. ; Zipprich, Alexander ; Triolo, Michela ; Maleux, Geert ; Fialla, Annette Dam ; Dam, Claus ; Vidal-González, Judit ; Majumdar, Avik ; Picón, Carmen ; Toth, Daniel ; Darnell, Anna ; Abraldes, Juan G. ; López, Marta ; Jansen, Christian ; Chang, Johannes ; Schierwagen, Robert ; Uschner, Frank Erhard ; Kukuk, Guido ; Meyer, Carsten ; Thomas, Daniel ; Wolter, Karsten ; Straßburg, Christian P. ; Laleman, Wim ; La Mura, Vincenzo ; Ripoll, Cristina ; Berzigotti, Annalisa ; Calleja, José Luis ; Tandon, Puneeta ; Hernández-Gea, Virginia ; Reiberger, Thomas ; Albillos, Agustin ; Tsochatzis, Emmanuel A. ; Krag, Aleksander ; Genescà, Joan ; Trebicka, Jonel
Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis.
Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint.
Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA.
Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis.
Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.
CD4+ T cell lymphopenia predicts mortality from Pneumocystis pneumonia in kidney transplant patients
(2020)
Freiwald, Tilo ; Büttner, Stefan ; Cheru, Nardos Tesfaye ; Avaniadi, Despina ; Martin, Simon S. ; Stephan, Christoph ; Pliquett, Rainer U. ; Asbe-Vollkopf, Aida ; Schüttfort, Gundolf ; Jacobi, Volkmar ; Herrmann, Eva ; Geiger, Helmut ; Hauser, Ingeborg A.
Background: Pneumocystis jirovecii pneumonia (PcP) remains a life-threatening opportunistic infection after solid organ transplantation, even in the era of Pneumocystis prophylaxis. The association between risk of developing PcP and low CD4+ T cell counts has been well established. However, it is unknown whether lymphopenia in the context of post-renal transplant PcP increases the risk of mortality. Methods: We carried out a retrospective analysis of a cohort of kidney transplant patients with PcP (n = 49) to determine the risk factors for mortality associated with PcP. We correlated clinical and demographic data with the outcome of the disease. For CD4+ T cell counts, we used the Wilcoxon rank sum test for in-hospital mortality and a Cox proportional-hazards regression model for 60-day mortality. Results: In univariate analyses, high CRP, high neutrophils, CD4+ T cell lymphopenia, mechanical ventilation, and high acute kidney injury network stage were associated with in-hospital mortality following presentation with PcP. In a receiver-operator characteristic (ROC) analysis, an optimum cutoff of ≤200 CD4+ T cells/µL predicted in-hospital mortality, CD4+ T cell lymphopenia remained a risk factor in a Cox regression model. Conclusions: Low CD4+ T cell count in kidney transplant recipients is a biomarker for disease severity and a risk factor for in-hospital mortality following presentation with PcP.
Adams, Joseph R. ; Aggarwal, Madan Mohan ; Ahammed, Zubayer ; Amonett, J. ; Anderson, B.D. ; Arkhipkin, D. ; Averichev, Georgy S. ; Badyal, S.K. ; Bai, Yu ; Balewski, J. ; Barannikova, O. ; Barnby, L.S. ; Baudot, J. ; Bekele, S. ; Belaga, V.V. ; Bellingeri-Laurikainen, A. ; Bellwied, Rene ; Berger, J. ; Bezverkhny, B.I. ; Bharadwaj, S. ; Bhasin, A. ; Bhati, A.K. ; Bhatia, V.S. ; Bichsel, Hans ; Bielcik, J. ; Bielcikova, Jana ; Billmeier, A. ; Bland, L.C. ; Blyth, C.O. ; Blyth, S.-L. ; Bonner, B.E. ; Botje, M. ; Boucham, A. ; Bouchet, J. ; Brandin, A.V. ; Bravar, A. ; Bystersky, M. ; Cadman, R.V. ; Cai, X.Z. ; Caines, Helen Louise ; Calderón de la Barca Sánchez, Manuel ; Castillo Castellanos, Javier Ernesto ; Catu, O. ; Cebra, D. ; Chajecki, Z. ; Chaloupka, Petr ; Chattopadhyay, S. ; Chen, H.F. ; Chen, J.H. ; Chen, Y. ; Cheng, J. ; Cherney, M. ; Chikanian, A. ; Choi, H.A. ; Christie, William ; Coffin, J.P. ; Cormier, Thomas Michael ; Cosentino, M.R. ; Cramer, J.G. ; Crawford, Henry J. ; Das, D. ; Das, S. ; Daugherity, M. ; de Moura, M.M. ; Dedovich, T.G. ; DePhillips, M. ; Derevschikov, Anatoly A. ; Didenko, Lidia ; Dietel, Thomas ; Dogra, S.M. ; Dong, W.J. ; Dong, X. ; Draper, J.E. ; Du, F. ; Dubey, A.K. ; Dunin, V.B. ; Dunlop, James C. ; Dutta Mazumdar, M.R. ; Eckardt, V. ; Edwards, W.R. ; Efimov, L.G. ; Emelianov, V. ; Engelage, Jon M. ; Eppley, Geary Wareham ; Erazmus, B. ; Estienne, M. ; Fachini, P. ; Faivre, J. ; Fatemi, Renee H. ; Fedorisin, J. ; Filimonov, K. ; Filip, P. ; Finch, Evan ; Fine, V. ; Fisyak, Yuri V. ; Fornazier, K.S.F. ; Fu, J. ; Gagliardi, Carl A. ; Gaillard, L. ; Gans, J. ; Ganti, M.S. ; Geurts, Frank ; Ghazikhanian, V. ; Ghosh, P. ; Gonzalez, Johan Enmanuel ; Gos, H. ; Grachov, O. ; Grebenyuk, O. ; Grosnick, David P. ; Guertin, S.M. ; Guo, Y. ; Gupta, Anik ; Gupta, N. ; Gutierrez, T.D. ; Hallman, T.J. ; Hamed, Ahmed M. ; Hardtke, D. ; Harris, John W. ; Heinz, M. ; Henry, T.W. ; Hepplemann, S. ; Hippolyte, Boris ; Hirsch, A. ; Hjort, E. ; Hoffmann, Gerald W. ; Horner, M.J. ; Huang, Huan Zhong ; Huang, Shengli ; Hughes, E.W. ; Humanic, Thomas J. ; Igo, G. ; Ishihara, A. ; Jacobs, P. ; Jacobs, William W. ; Jedynak, M. ; Jiang, H. ; Jones, Peter Graham ; Judd, Eleanor G. ; Kabana, Sonia ; Kang, K. ; Kaplan, M. ; Keane, Declan ; Kechechyan, A. ; Khodyrev, V.Yu. ; Kim, B.C. ; Kiryluk, J. ; Kisiel, A. ; Kislov, E.M. ; Klay, J. ; Klein, S.R. ; Koetke, D.D. ; Kollegger, Thorsten ; Kopytine, M. ; Kotchenda, L. ; Kowalik, K.L. ; Kramer, M. ; Kravtsov, P. ; Kravtsov, V.I. ; Krueger, Keith William ; Kuhn, C. ; Kulikov, A.I. ; Kumar, A. ; Kutuev, R.Kh. ; Kuznetsov, A.A. ; Lamont, Matthew A. C. ; Landgraf, Jeffery M. ; Lange, S. ; Laue, F. ; Lauret, Jerome ; Lebedev, A. ; Lednicky, R. ; Lee, C.-H. ; Lehocka, S. ; LeVine, M.J. ; Li, C. ; Li, Q. ; Li, Y. ; Lin, G. ; Lindenbaum, S.J. ; Lisa, Michael A. ; Liu, F. ; Liu, H. ; Liu, J. ; Liu, L. ; Liu, Q.J. ; Liu, Z. ; Ljubicic, Tonko A. ; Llope, W.J. ; Long, H. ; Longacre, Ronald S. ; Lopez-Noriega, M. ; Love, W.A. ; Lu, Y. ; Ludlam, Thomas ; Lynn, D. ; Ma, G.L. ; Ma, J.G. ; Ma, Y.G. ; Magestro, D. ; Mahajan, Sanjay ; Mahapatra, Durga Prasad ; Majka, R. ; Mangotra, L.K. ; Manweiler, R. ; Margetis, Spyridon ; Markert, Christina ; Martin, L. ; Marx, Jay N. ; Matis, Howard S. ; Matulenko, Yu.A. ; McClain, C.J. ; McShane, T.S. ; Meissner, F. ; Melnick, Yu. ; Meschanin, A. ; Miller, M.L. ; Minaev, N.G. ; Mironov, C. ; Mischke, A. ; Mishra, D.K. ; Mitchell, J. ; Mohanty, Bedangadas ; Molnar, L. ; Moore, C.F. ; Morozov, D.A. ; Munhoz, M.G. ; Nandi, B.K. ; Nayak, S.K. ; Nayak, T.K. ; Nelson, John M. ; Netrakanti, P.K. ; Nikitin, V.A. ; Nogach, L.V. ; Nurushev, S.B. ; Odyniec, Grazyna Janina ; Ogawa, Akio ; Okorokov, Vitaly A. ; Oldenburg, Markus D. ; Olson, D. ; Pal, S.K. ; Panebratsev, Yuri ; Panitkin, Sergei Yurievich ; Pavlinov, A.I. ; Pawlak, T. ; Peitzmann, Thomas ; Perevoztchikov, V. ; Perkins, Chris ; Peryt, W. ; Petrov, V.A. ; Phatak, S.C. ; Picha, R. ; Planinic, Mirko ; Pluta, Jan Marian ; Porile, Norbert T. ; Porter, J. ; Poskanzer, Arthur M. ; Potekhin, M. ; Potrebenikova, E. ; Potukuchi, B.V.K.S. ; Prindle, Duncan J. ; Pruneau, Claude A. ; Putschke, Jörn H. ; Rakness, G. ; Raniwala, R. ; Raniwala, S. ; Ravel, O. ; Ray, Robert L. ; Razin, S.V. ; Reichhold, D. ; Reid, Jeffrey G. ; Reinnarth, J. ; Renault, G. ; Retiere, F. ; Ridiger, A. ; Ritter, Hans Georg ; Roberts, J.B. ; Rogachevskiy, O.V. ; Romero, J.L. ; Rose, A. ; Roy, C. ; Ruan, L. ; Russcher, M.J. ; Sahoo, R. ; Sakrejda, I. ; Salur, Sevil ; Sandweiss, J. ; Sarsour, M. ; Savin, I. ; Sazhin, P.S. ; Schambach, Joachim ; Scharenberg, Rolf Paul ; Schmitz, Norbert ; Schweda, Kai ; Seger, J. ; Seyboth, P. ; Shahaliev, E. ; Shao, M. ; Shao, W. ; Sharma, M. ; Shen, W.Q. ; Shestermanov, K.E. ; Shimanskiy, S.S. ; Sichtermann, E. ; Simon, F. ; Singaraju, R.N. ; Smirnov, Nikolai ; Snellings, Raimond ; Sood, G. ; Sorensen, P. ; Sowinski, James ; Speltz, J. ; Spinka, Harold. M. ; Srivastava, B. ; Stadnik, A. ; Stanislaus, T.D.S. ; Stock, Reinhard ; Stolpovsky, A. ; Strikhanov, M. ; Stringfellow, B. ; Suaide, Alexandre Alarcon do Passo ; Sugarbaker, E. ; Šumbera, Michal ; Surrow, Bernd ; Swanger, M. ; Symons, T.J.M. ; Szanto de Toledo, A. ; Tai, A. ; Takahashi, Jun ; Tang, Aihong ; Tarnowsky, Terence J. ; Thein, D. ; Thomas, James H. ; Timmins, Anthony Robert ; Timoshenko, S. ; Tokarev, M. ; Trainor, T.A. ; Trentalange, Stephen ; Tribble, Robert E. ; Tsai, Oleg D. ; Ulery, J. ; Ullrich, Thomas ; Underwood, David G. ; Van Buren, Gene ; Kolk, Naomi van der ; Leeuwen, Marco van ; Vander Molen, A.M. ; Varma, R. ; Vasilevski, I.M. ; Vasiliev, A.N. ; Vernet, R. ; Vigdor, S.E. ; Viyogi, Y.P. ; Vokal, S. ; Voloshin, Sergei ; Waggoner, W.T. ; Wang, F. ; Wang, G. ; Wang, G. ; Wang, X.L. ; Wang, Y. ; Wang, Y. ; Wang, Z.M. ; Ward, H. ; Watson, J.W. ; Webb, J.C. ; Westfall, Gary D. ; Wetzler, Alexander Albert ; Whitten, Charles A. ; Wieman, Howard ; Wissink, Scott W. ; Witt, Richard ; Wood, J. ; Wu, J. ; Xu, N. ; Xu, Z. ; Xu, Z.Z. ; Yamamoto, E. ; Yepes, P. ; Yoo, I.-K. ; Yurevich, V.I. ; Zborovsky, I. ; Zhang, H. ; Zhang, W.M. ; Zhang, Y. ; Zhang, Z.P. ; Zhong, C. ; Zoulkarneev, R. ; Zoulkarneeva, Youlia ; Zubarev, A.N. ; Zuo, J.X.
We present the first measurements of charge-dependent correlations on angular difference variables η1 − η2 (pseudorapidity) and φ1 − φ2 (azimuth) for primary charged hadrons with transverse momentum 0.15 <= pt <= 2 GeV/c and |η| <= 1.3 from Au–Au collisions at √sNN = 130 GeV. We observe correlation structures not predicted by theory but consistent with evolution of hadron emission geometry with increasing centrality from one-dimensional fragmentation of color strings along the beam direction to an at least two-dimensional hadronization geometry along the beam and azimuth directions of a hadron-opaque bulk medium.
Dietrich, Sascha ; Oleś, Małgorzata ; Lu, Junyan ; Sellner, Leopold ; Anders, Simon ; Velten, Britta ; Wu, Bian ; Hüllein, Jennifer ; Silva Liberio, Michelle da ; Walther, Tatjana ; Wagner, Lena ; Rabe, Sophie ; Ghidelli-Disse, Sonja ; Bantscheff, Marcus ; Oleś, Andrzej K. ; Słabicki, Mikołaj ; Mock, Andreas ; Oakes, Christopher C. ; Wang, Shihui ; Oppermann, Sina ; Lukas, Marina ; Kim, Vladislav ; Sill, Martin ; Benner, Axel ; Jauch, Anna ; Sutton, Lesley-Ann ; Young, Emma ; Rosenquist, Richard ; Liu, Xiyang ; Jethwa, Alexander ; Lee, Kwang Seok ; Lewis, Joe ; Putzker, Kerstin ; Lutz, Christoph ; Rossi, Davide ; Mokhir, Andriy ; Oellerich, Thomas ; Zirlik, Katja ; Herling, Marco ; Nguyen-Khac, Florence ; Plass, Christoph ; Andersson, Emma ; Mustjoki, Satu ; Kalle, Christof von ; Ho, Anthony Dick ; Hensel, Manfred ; Dürig, Jan ; Ringshausen, Ingo ; Zapatka, Marc ; Huber, Wolfgang ; Zenz, Thorsten
As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
Poms, Martin ; Ansorge, Philipp ; Martinez-Gil, Luis ; Jurt, Simon ; Gottstein, Daniel ; Fracchiolla, Katrina E. ; Cohen, Leah S. ; Güntert, Peter ; Mingarro, Ismael ; Naider, Fred ; Zerbe, Oliver
Folding of G-protein coupled receptors (GPCRs) according to the two-stage model (Popot, J. L., and Engelman, D. M. (1990) Biochemistry 29, 4031–4037) is postulated to proceed in 2 steps: partitioning of the polypeptide into the membrane followed by diffusion until native contacts are formed. Herein we investigate conformational preferences of fragments of the yeast Ste2p receptor using NMR. Constructs comprising the first, the first two, and the first three transmembrane (TM) segments, as well as a construct comprising TM1–TM2 covalently linked to TM7 were examined. We observed that the isolated TM1 does not form a stable helix nor does it integrate well into the micelle. TM1 is significantly stabilized upon interaction with TM2, forming a helical hairpin reported previously (Neumoin, A., Cohen, L. S., Arshava, B., Tantry, S., Becker, J. M., Zerbe, O., and Naider, F. (2009) Biophys. J. 96, 3187–3196), and in this case the protein integrates into the hydrophobic interior of the micelle. TM123 displays a strong tendency to oligomerize, but hydrogen exchange data reveal that the center of TM3 is solvent exposed. In all GPCRs so-far structurally characterized TM7 forms many contacts with TM1 and TM2. In our study TM127 integrates well into the hydrophobic environment, but TM7 does not stably pack against the remaining helices. Topology mapping in microsomal membranes also indicates that TM1 does not integrate in a membrane-spanning fashion, but that TM12, TM123, and TM127 adopt predominantly native-like topologies. The data from our study would be consistent with the retention of individual helices of incompletely synthesized GPCRs in the vicinity of the translocon until the complete receptor is released into the membrane interior.
Marggrander, Daniel Tobias ; Koç-Günel, Sinem ; Tekeli-Camcı, Nesrin ; Martin, Simon ; Golbach, Rejane ; Wolf, Timo
Objectives: To prospectively evaluate lung ultrasound in comparison with radiography and computed tomography (CT) for detecting HIV-related lung diseases.
Methods: Ultrasound examinations in HIV-positive patients were evaluated by three raters; available conventional imaging was evaluated by another rater. Results were compared with each other and the definite diagnosis. Interrater reliability was calculated for each finding.
Results: Eighty HIV-positive patients received lung ultrasound examinations; 74 received conventional imaging. The overall sensitivity was 97.5% for CT, 90.7% for ultrasound and 78.1% for radiography. The most common diagnoses were Pneumocystis jirovecii pneumonia (21 cases) and bacterial pneumonia (17 cases). The most frequent and sensitive ultrasonographic findings were interstitial abnormalities indicated by B-lines, independent of the aetiology. Interrater reliability was high for interstitial abnormalities (ICC=0.82). The interrater reliability for consolidations and effusion increased during the study (r=0.88 and r=0.37, respectively).
Conclusions: Ultrasound is a fast, reliable and sensitive point-of-care tool, particularly in detecting interstitial lung disease, which is common in HIV-associated illness. It does not effectively discriminate between different aetiologies. A longer learning period might be required to reliably identify consolidations and effusions.
In recent years, many European cities have developed strategies to improve the quality of urban life by reducing car traffic and increasing the attractiveness of alternative modes and the built environment for residents. Frequently, at least in German cities, improvements to the cycling infrastructures play a key role in this transformation of urban spaces. One of those transformative interventions took place in 2020 in Frankfurt am Main (Germany). The city redesigned an arterial road close to the city centre, the Friedberger Landstrasse, by converting two car lanes to bicycle lanes. It is the aim of this study to analyse the effects of this change on the quality of urban life of its residents using a quantitative before-and-after study. The results demonstrate the expected improvements in the perceived quality of urban life for residents after the intervention. A more detailed analysis, however, shows that the residents’ perceptions vary according to their own mode use on the Friedberger Landstrasse and other sociodemographic characteristics. Thus, better cycling infrastructure does not only improve conditions for cyclists, but also contributes to a higher quality of urban life for residents and, therefore, improves the liveability of a city in two ways. We conclude that local transport policies are not only relevant for a modal shift, but also for the quality of urban life and, thus, related urban development strategies.
Everett, Derek ; Ke, Weiyao ; Paquet, Jean-François ; Vujanovic, Gojko ; Bass, Steffen A. ; Du, Lipei ; Gale, Charles ; Heffernan, Matthew ; Heinz, Ulrich ; Liyanage, Dananjaya ; Luzum, Matthew ; Majumder, Abhijit ; McNelis, Michael ; Shen, Chun ; Xu, Yichun ; Angerami, Aaron ; Cao, Shanshan ; Chen, Y. ; Coleman, Jonathon ; Cunqueiro, Leticia ; Dai, Tianyu ; Ehlers, Raymond ; Elfner, Hannah ; Fan, Wang ; Fries, Rainer J. ; Garza, Fabian ; He, Yayun ; Jacak, Barbara V. ; Jacobs, Peter Martin ; Jeon, Sangyong ; Kim, B. ; Kordell, Michael ; Kumar, Amit ; Mak, Simon ; Mulligan, James D. ; Nattrass, Christine ; Oliinychenko, Dmytro ; Park, Chanwook ; Putschke, Jörn H. ; Roland, Gunther ; Schenke, Björn Peter ; Schwiebert, Loren ; Silva, A. ; Sirimanna, Chathuranga ; Soltz, Ron Ariel ; Tachibana, Yasuki ; Wang, Xin-Nian ; Wolpert, Robert L.
Using combined data from the Relativistic Heavy Ion and Large Hadron Colliders, we constrain the shear and bulk viscosities of quark-gluon plasma (QGP) at temperatures of ∼150–350 MeV. We use Bayesian inference to translate experimental and theoretical uncertainties into probabilistic constraints for the viscosities. With Bayesian model averaging we propagate an estimate of the model uncertainty generated by the transition from hydrodynamics to hadron transport in the plasma’s final evolution stage, providing the most reliable phenomenological constraints to date on the QGP viscosities.
SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy
(2017)
De Colle, Chiara ; Mönnich, David ; Welz, Stefan ; Böke, Simon ; Sipos, Bence ; Fend, Falko ; Mauz, Paul-Stefan ; Tinhofer, Inge ; Budach, Volker ; Abu Jawad, Jehad ; Stuschke, Martin ; Balermpas, Panagiotis ; Rödel, Claus ; Grosu, Anca-Ligia ; Abdollahi, Amir ; Debus, Jürgen ; Bayer, Christine ; Belka, Claus ; Pigorsch, Steffi ; Combs, Stephanie ; Lohaus, Fabian ; Linge, Annett ; Krause, Mechthild ; Baumann, Michael ; Zips, Daniel ; Menegakis, Apostolos
Introduction: Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Material and methods: Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data.
Results: In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found.
Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.
Koch, Vitali ; Grünewald, Leon David ; Gruber-Rouh, Tatjana ; Martin, Simon ; Eichler, Katrin ; Booz, Christian ; Yel, Ibrahim ; Vogl, Thomas J. ; Buchner, Kristina ; Hagenmueller, Marco ; März, Winfried ; Frey, Norbert ; Hardt, Stefan ; Riffel, Johannes
Low serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms. This study sought to assess the influence of HA on cardiac remodeling in rats undergoing either transaortic banding or inhibition of nitric oxide synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Male Wistar rats (n = 136) underwent sham operation (SH) or aortic banding (AB). Both groups were equally divided into 14 subgroups, receiving different doses of HA alone or in combination with lisinopril, spironolactone, or L-NAME for 4 weeks. HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg−1·day−1. Combining 800 mg·kg−1·day−1 HA with spironolactone or lisinopril yielded additional effects, showing a positive correlation with LV ejection fraction (+33%, p = 0.0002) and fractional shortening (+41%, p = 0.0014). An inverse association was observed with collagen area fraction (−41%, p < 0.0001), myocyte cross-sectional area (−22%, p < 0.0001) and the molecular markers atrial natriuretic factor (−74%, p = 0.0091), brain natriuretic peptide (−42%, p = 0.0298), beta-myosin heavy chain (−46%, p = 0.0411), and collagen type V alpha 1 chain (−73%, p = 0.0257) compared to placebo-treated AB animals. Co-administration of HA and L-NAME was found to attenuate cardiac remodeling and prevent NO-deficient hypertension following AB. HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes in cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in additional beneficial effects boosting its direct impact on heart failure pathophysiology.
Peter, Antonia Sophia ; Roth, Edith ; Schulz, Sebastian R. ; Fraedrich, Kirsten ; Steinmetz, Tobit ; Damm, Dominik ; Hauke, Manuela ; Richel, Elie ; Müller-Schmucker, Sandra ; Habenicht, Katharina ; Eberlein, Valentina ; Issmail, Leila ; Uhlig, Nadja ; Dolles, Simon ; Grüner, Eva ; Peterhoff, David ; Ciesek, Sandra ; Hoffmann, Markus ; Pöhlmann, Stefan ; McKay, Paul F. ; Shattock, Robin J. ; Wölfel, Roman ; Socher, Eileen ; Wagner, Ralf ; Eichler, Jutta ; Sticht, Heinrich ; Schuh, Wolfgang ; Neipel, Frank ; Ensser, Armin ; Mielenz, Dirk Alexander ; Tenbusch, Matthias ; Winkler, Thomas H. ; Grunwald, Thomas ; Überla, Klaus Thomas ; Jäck, Hans-Martin
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Summary: Understanding the role of short-interfering RNA (siRNA) in diverse biological processes is of current interest and often approached through small RNA sequencing. However, analysis of these datasets is difficult due to the complexity of biological RNA processing pathways, which differ between species. Several properties like strand specificity, length distribution, and distribution of soft-clipped bases are few parameters known to guide researchers in understanding the role of siRNAs. We present RAPID, a generic eukaryotic siRNA analysis pipeline, which captures information inherent in the datasets and automatically produces numerous visualizations as user-friendly HTML reports, covering multiple categories required for siRNA analysis. RAPID also facilitates an automated comparison of multiple datasets, with one of the normalization techniques dedicated for siRNA knockdown analysis, and integrates differential expression analysis using DESeq2. RAPID is available under MIT license at https://github.com/SchulzLab/RAPID. We recommend using it as a conda environment available from https://anaconda.org/bioconda/rapid.
Understanding the role of short-interfering RNA (siRNA) in diverse biological processes is of current interest and often approached through small RNA sequencing. However, analysis of these datasets is difficult due to the complexity of biological RNA processing pathways, which differ between species. Several properties like strand specificity, length distribution, and distribution of soft-clipped bases are few parameters known to guide researchers in understanding the role of siRNAs. We present RAPID, a generic eukaryotic siRNA analysis pipeline, which captures information inherent in the datasets and automatically produces numerous visualizations as user-friendly HTML reports, covering multiple categories required for siRNA analysis. RAPID also facilitates an automated comparison of multiple datasets, with one of the normalization techniques dedicated for siRNA knockdown analysis, and integrates differential expression analysis using DESeq2.
Koch, Vitali ; Grünewald, Leon David ; Albrecht, Moritz Hans Ernst ; Eichler, Katrin ; Gruber-Rouh, Tatjana ; Yel, Ibrahim ; Alizadeh, Leona Soraja ; Mahmoudi, Scherwin ; Scholtz, Jan-Erik ; Martin, Simon S. ; Lenga, Lukas ; Vogl, Thomas J. ; Mohammed, Nour-Eldin Abdelrehim Nour-Eldin ; Bienenfeld, Florian ; Hammerstingl, Renate Maria ; Graf, Christiana ; Sommer, Christof M. ; Hardt, Stefan ; Mazziotti, Silvio ; Ascenti, Giorgio ; Versace, Giovanni Antonio ; D’Angelo, Tommaso ; Booz, Christian
Highlights
• Assessment of coronary artery plaque burden according to the CAC-DRS Score correlated well with pulmonary involvement of SARS-CoV-2 pneumonia (min. r=0.81, 95% CI 0.76 to 0.86).
• Visual and quantitative CAC-DRS Score of coronary artery plaque burden provided independent prognostic information on all-cause mortality in patients with SARS-CoV-2 pneumonia (p=0.0016 and p<0.0001, respectively).
• Incorporating CAC-DRS Score and pulmonary involvement into clinical decision making revealed great potential to discriminate patients with fatal outcomes from a mild course of disease (AUC 0.938, 95% CI 0.89 to 0.97) and the need for intensive care treatment (AUC 0.801, 95% CI 0.77 to 0.83).
Purpose: To assess and correlate pulmonary involvement and outcome of SARS-CoV-2 pneumonia with the degree of coronary plaque burden based on the CAC-DRS classification (Coronary Artery Calcium Data and Reporting System).
Methods: This retrospective study included 142 patients with confirmed SARS-CoV-2 pneumonia (58 ± 16 years; 57 women) who underwent non-contrast CT between January 2020 and August 2021 and were followed up for 129 ± 72 days. One experienced blinded radiologist analyzed CT series for the presence and extent of calcified plaque burden according to the visual and quantitative HU-based CAC-DRS Score. Pulmonary involvement was automatically evaluated with a dedicated software prototype by another two experienced radiologists and expressed as Opacity Score.
Results: CAC-DRS Scores derived from visual and quantitative image evaluation correlated well with the Opacity Score (r=0.81, 95% CI 0.76-0.86, and r=0.83, 95% CI 0.77-0.89, respectively; p<0.0001) with higher correlation in severe than in mild stage SARS-CoV-2 pneumonia (p<0.0001). Combined, CAC-DRS and Opacity Scores revealed great potential to discriminate fatal outcomes from a mild course of disease (AUC 0.938, 95% CI 0.89-0.97), and the need for intensive care treatment (AUC 0.801, 95% CI 0.77-0.83). Visual and quantitative CAC-DRS Scores provided independent prognostic information on all-cause mortality (p=0.0016 and p<0.0001, respectively), both in univariate and multivariate analysis.
Conclusions: Coronary plaque burden is strongly correlated to pulmonary involvement, adverse outcome, and death due to respiratory failure in patients with SARS-CoV-2 pneumonia, offering great potential to identify individuals at high risk.
Reschke, Philipp ; Gotta, Jennifer ; Stahl, Adrian ; Koch, Vitali ; Mader, Christoph ; Martin, Simon S. ; Scholtz, Jan-Erik ; Booz, Christian ; Yel, Ibrahim ; Hescheler, Daniel Alexander Adalbert ; Gruber-Rouh, Tatjana ; Eichler, Katrin ; Vogl, Thomas J. ; Grünewald, Leon David
Rationale and Objectives: Bone non-union is a serious complication of distal radius fractures (DRF) that can result in functional limitations and persistent pain. However, no accepted method has been established to identify patients at risk of developing bone non-union yet. This study aimed to compare various CT-derived metrics for bone mineral density (BMD) assessment to identify predictive values for the development of bone non-union.
Materials and Methods: CT images of 192 patients with DRFs who underwent unenhanced dual-energy CT (DECT) of the distal radius between 03/2016 and 12/2020 were retrospectively identified. Available follow-up imaging and medical health records were evaluated to determine the occurrence of bone non-union. DECT-based BMD, trabecular Hounsfield unit (HU), cortical HU and cortical thickness ratio were measured in normalized non-fractured segments of the distal radius.
Results: Patients who developed bone non-union were significantly older (median age 72 years vs. 54 years) and had a significantly lower DECT-based BMD (median 68.1 mg/cm3 vs. 94.6 mg/cm3, p < 0.001). Other metrics (cortical thickness ratio, cortical HU, trabecular HU) showed no significant differences. ROC and PR curve analyses confirmed the highest diagnostic accuracy for DECT-based BMD with an area under the curve (AUC) of 0.83 for the ROC curve and an AUC of 0.46 for the PR curve. In logistic regression models, DECT-based BMD was the sole metric significantly associated with bone non-union.
Conclusion: DECT-derived metrics can accurately predict bone non-union in patients who sustained DRF. The diagnostic performance of DECT-based BMD is superior to that of HU-based metrics and cortical thickness ratio.
Patil, Shivaprasad ; Linge, Annett ; Hiepe, Hannah ; Grosser, Marianne ; Lohaus, Fabian ; Gudziol, Volker ; Kemper, Max ; Nowak, Alexander ; Haim, Dominik ; Tinhofer, Ingeborg ; Budach, Volker ; Guberina, Maja ; Stuschke, Martin ; Balermpas, Panagiotis ; Müller-von der Grün, Jens ; Schäfer, Henning Sebastian ; Grosu, Anca-Ligia ; Abdollahi, Amir ; Debus, Jürgen ; Ganswindt, Ute ; Belka, Claus ; Pigorsch, Steffi Ulrike ; Combs, Stephanie ; Böke, Simon ; Zips, Daniel ; Jöhrens, Korinna ; Baretton, Gustavo Bruno ; Baumann, Michael ; Krause, Mechthild ; Löck, Steffen
(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.