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Journal articles on the topic 'HDR multiple exposures'

Author: Grafiati
Published: 4 June 2021
Last updated: 1 February 2022

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1

Xie, Shundao, Wenfang Wu, Rongjun Chen, and Hong-Zhou Tan. "Reduced-Dimensional Capture of High-Dynamic Range Images with Compressive Sensing." Discrete Dynamics in Nature and Society 2020 (April 27, 2020): 1–13. http://dx.doi.org/10.1155/2020/6703528.

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The range of light illumination in real scenes is very large, and ordinary cameras can only record a small part of this range, which is far lower than the range of human eyes’ perception of light. High-dynamic range (HDR) imaging technology that has appeared in recent years can record a wider range of illumination than the perceptual range of the human eye. However, the current mainstream HDR imaging technology is to capture multiple low-dynamic range (LDR) images of the same scene with different exposures and then merge them into one HDR image, which greatly increases the amount of data captured. The advent of single-pixel cameras (compressive imaging system) has proved the feasibility of obtaining and restoring image data based on compressive sensing. Therefore, this paper proposes a method for reduced-dimensional capture of high dynamic range images with compressive sensing, which includes algorithms for front end (capturing) and back end (processing). At the front end, the K-SVD dictionary is used to compressive sensing the input multiple-exposure image sequence, thereby reducing the amount of data transmitted to the back end. At the back end, the Orthogonal Matching Pursuit (OMP) algorithm is used to reconstruct the input multiple-exposure image sequence. A low-rank PatchMatch algorithm is proposed to merge the reconstructed image sequence to obtain an HDR image. Simulation results show that, under the premise of reducing the complexity of the front-end equipment and the amount of communication data between the front end and the back end, the overall system achieves a good balance between the amount of calculation and the quality of the HDR image obtained.
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2

Pizág, Bertalan, and Balázs Vince Nagy. "Extrapolation of Saturated Diffraction Spikes in Photographs Containing Light Sources." Periodica Polytechnica Mechanical Engineering 64, no. 3 (June 29, 2020): 233–39. http://dx.doi.org/10.3311/ppme.16044.

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The observed luminance of most light sources is many orders of magnitude higher than the luminance of surrounding objects and the background. With the dynamic range of single photographs limited to 8 to 10 bits, both dark and bright values are radically coerced to the limits. This problem is usually circumvented with the use of High-Dynamic-Range (HDR) imaging, assembling multiple photographs of the same scene made at different exposures. But in some situations, or due to equipment limitations, HDR imaging might not be possible. This research is aimed at the extrapolation of luminance peaks within oversaturated Low-Dynamic-Range (LDR) images. The proposed method of extrapolation relies on the identification and analysis of Fraunhofer diffraction patterns created by the aperture. The algorithm is tested on a set of HDR images containing one or two lamps. These images are converted to LDR at a custom saturation cap, then extrapolated to restore the original peaks with relative success.
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Gil Rodríguez, R., J. Vazquez-Corral, and M. Bertalmío. "Issues with Common Assumptions about the Camera Pipeline and Their Impact in HDR Imaging from Multiple Exposures." SIAM Journal on Imaging Sciences 12, no. 4 (January 2019): 1627–42. http://dx.doi.org/10.1137/19m1250248.

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Eisemann, Leon, Jan Froehlich, Axel Hartz, and Johannes Maucher. "Expanding dynamic range in a single-shot image through a sparse grid of low exposure pixels." Electronic Imaging 2020, no. 7 (January 26, 2020): 229–1. http://dx.doi.org/10.2352/issn.2470-1173.2020.7.iss-229.

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Camera sensors are physically restricted in the amount of luminance which can be captured at once. To achieve a higher dynamic range, multiple exposures are typically combined. This method comes with several disadvantages, like temporal or alignment aliasing. Hence, we propose a method to preserve high luminance information in a single-shot image. By introducing a grid of highlight preserving pixels, which equals 1% of the total amount of pixels, we are able to sustain information directly incamera for later processing. To provide evidence, that this number of pixels is enough for gaining additional dynamic range, we use a U-Net for reconstruction. For training, we make use of the HDR+ dataset, which we augment to simulate our proposed grid. We demonstrate that our approach can preserve high luminance information, which can be used for a visually convincing reconstruction, close to the ground truth.
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Tahiri, Iasim, Yaiza Garro-Aguilar, Valerie Cayssials, David Achaintre, Francesca Romana Mancini, Yahya Mahamat-Saleh, Marie-Christine Boutron-Ruault, et al. "Urinary flavanone concentrations as biomarkers of dietary flavanone intakes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study." British Journal of Nutrition 123, no. 6 (December 3, 2019): 691–98. http://dx.doi.org/10.1017/s0007114519003131.

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AbstractIn the present study, the aim was to investigate the correlation between the acute and habitual dietary intake of flavanones, their main food sources and the concentrations of aglycones naringenin and hesperetin in 24 h urine in a European population. A 24-h dietary recall (24-HDR) and a 24-h urine sample were collected the same day from a subsample of 475 people from four different countries of the European Prospective Investigation into Cancer and Nutrition study. Acute and habitual dietary data were captured through a standardised 24-HDR and a country/centre-specific validated dietary questionnaire (DQ). The intake of dietary flavanones was estimated using the Phenol-Explorer database. Urinary flavanones (naringenin and hesperetin) were analysed using tandem MS with a previous enzymatic hydrolysis. Weak partial correlation coefficients were found between urinary flavanone concentrations and both acute and habitual dietary flavanone intakes (Rpartial = 0·14–0·17). Partial correlations were stronger between urinary excretions and acute intakes of citrus fruit and juices (Rpartial ∼ 0·6) than with habitual intakes of citrus fruit and juices (Rpartial ∼ 0·24). In conclusion, according to our results, urinary excretion of flavanones can be considered a good biomarker of acute citrus intake. However, low associations between habitual flavanone intake and urinary excretion suggest a possible inaccurate estimation of their intake or a too sporadic intake. For assessing habitual exposures, multiple urinary collections may be needed. These results show that none of the approaches tested is ideal, and the use of both DQ and biomarkers can be recommended.
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Choi, Ho-Hyoung, Hyun-Soo Kang, and Byoung-Ju Yun. "Tone Mapping of High Dynamic Range Images Combining Co-Occurrence Histogram and Visual Salience Detection." Applied Sciences 9, no. 21 (November 1, 2019): 4658. http://dx.doi.org/10.3390/app9214658.

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One of the significant qualities of the human vision, which differentiates it from computer vision, is so called attentional control, which is the innate ability of our human eyes to select what visual stimuli to pay attention to at any moment in time. In this sense, the visual salience detection model, which is designed to simulate how the human visual system (HVS) perceives objects and scenes, is widely used for performing multiple vision tasks. This model is also in high demand in the tone mapping technology of high dynamic range images (HDRIs). Another distinct quality of the HVS is that our eyes blink and adjust brightness when objects are in their sight. Likewise, HDR imaging is a technology applied to a camera that takes pictures of an object several times by repeatedly opening and closing a camera iris, which is referred to as multiple exposures. In this way, the computer vision is able to control brightness and depict a range of light intensities. HDRIs are the product of HDR imaging. This article proposes a novel tone mapping method using CCH-based saliency-aware weighting and edge-aware weighting methods to efficiently detect image salience information in the given HDRIs. The two weighting methods combine with a guided filter to generate a modified guided image filter (MGIF). The function of the MGIF is to split an image into the base layer and the detail layer which are the two elements of an image: illumination and reflection, respectively. The base layer is used to obtain global tone mapping and compress the dynamic range of HDRI while preserving the sharp edges of an object in the HDRI. This has a remarkable effect of reducing halos in the resulting HDRIs. The proposed approach in this article also has several distinct advantages of discriminative operation, tolerance to image size variation, and minimized parameter tuning. According to the experimental results, the proposed method has made progress compared to its existing counterparts when it comes to subjective and quantitative qualities, and color reproduction.
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Merianos, Ioannis, and Nikolaos Mitianoudis. "Multiple-Exposure Image Fusion for HDR Image Synthesis Using Learned Analysis Transformations." Journal of Imaging 5, no. 3 (February 26, 2019): 32. http://dx.doi.org/10.3390/jimaging5030032.

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Modern imaging applications have increased the demand for High-Definition Range (HDR) imaging. Nonetheless, HDR imaging is not easily available with low-cost imaging sensors, since their dynamic range is rather limited. A viable solution to HDR imaging via low-cost imaging sensors is the synthesis of multiple-exposure images. A low-cost sensor can capture the observed scene at multiple-exposure settings and an image-fusion algorithm can combine all these images to form an increased dynamic range image. In this work, two image-fusion methods are combined to tackle multiple-exposure fusion. The luminance channel is fused using the Mitianoudis and Stathaki (2008) method, while the color channels are combined using the method proposed by Mertens et al. (2007). The proposed fusion algorithm performs well without halo artifacts that exist in other state-of-the-art methods. This paper is an extension version of a conference, with more analysis on the derived method and more experimental results that confirm the validity of the method.
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8

Varkonyi-Koczy, A. R., A. Rovid, and T. Hashimoto. "Gradient-Based Synthesized Multiple Exposure Time Color HDR Image." IEEE Transactions on Instrumentation and Measurement 57, no. 8 (August 2008): 1779–85. http://dx.doi.org/10.1109/tim.2008.925715.

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9

Jiang, Xianwu, Qingyi Gu, Tadayoshi Aoyama, Takeshi Takaki, and Idaku Ishii. "A High-Speed Vision System with Multithread Automatic Exposure Control for High-Dynamic-Range Imaging." Journal of Robotics and Mechatronics 30, no. 1 (February 20, 2018): 117–27. http://dx.doi.org/10.20965/jrm.2018.p0117.

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In this study, we develop a real-time high-frame-rate vision system with frame-by-frame automatic exposure (AE) control that can simultaneously synthesize multiple images with different exposure times into a high-dynamic-range (HDR) image for scenarios with dynamic change in illumination. By accelerating the video capture and processing for time-division multithread AE control at the millisecond level, the proposed system can virtually function as multiple AE cameras with different exposure times. This system can capture color HDR images of 512 × 512 pixels in real time at 500 fps by synthesizing four 8-bit color images with different exposure times at consecutive frames, captured at an interval of 2 ms, with pixel-level parallel processing accelerated by a GPU (Graphic Processing Unit) board. Several experimental results for scenarios with a large change in illumination are demonstrated to confirm the performance of the proposed system for real-time HDR imaging.
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10

Kiran, Bagadi Ravi, Vatsavayi Valli Kumari, and KVSVN Raju. "Model for High Dynamic Range Imaging System Using Hybrid Feature Based Exposure Fusion." Journal of Intelligent Systems 30, no. 1 (October 13, 2020): 346–60. http://dx.doi.org/10.1515/jisys-2018-0412.

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Abstract The luminous value is high for many natural scenes, which causes loss of information and occurs in dark images. The High Dynamic Range (HDR) technique captures the same objects or scene for multiple times in different exposure and produces the images with proper illumination. This technique is used in the various applications such as medical imaging and observing the skylight, etc. HDR imaging techniques usually have the issue of lower efficiency due to capturing of multiple photos. In this paper, an efficient method is proposed for HDR imaging technique to achieve better performance and lower noise. The Luminance-Chrominance-Gradient High Dynamic Range (LCGHDR) method is proposed to obtain the proper luminous value of images. The same scenario is captured at different exposure are processed by the proposed method. Based on these feature values extracted from the different images and exposure fusion technique was developed that helps for the proper imaging. This experiment was evaluated and analyzed by comparing with the other methods, which showed the efficiency of the proposed method. This method needs only 124.594 seconds for the computation, while existing method need 139.869 seconds for the same number of images.
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11

Al_airaji, Roa'a M., Ibtisam A. Aljazaery, Suha Kamal Al_Dulaimi, and Haider TH Salim Alrikabi. "Generation of high dynamic range for enhancing the panorama environment." Bulletin of Electrical Engineering and Informatics 10, no. 1 (February 1, 2021): 138–47. http://dx.doi.org/10.11591/eei.v10i1.2362.

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This paper presents a methodology for enhancement of panorama images environment by calculating high dynamic range. Panorama is constructing by merge of several photographs that are capturing by traditional cameras at different exposure times. Traditional cameras usually have much lower dynamic range compared to the high dynamic range in the real panorama environment, where the images are captured with traditional cameras will have regions that are too bright or too dark. A more details will be visible in bright regions with a lower exposure time and more details will be visible in dark regions with a higher exposure time. Since the details in both bright and dark regions cannot preserve in the images that are creating using traditional cameras, the proposed system have to calculate one using the images that traditional camera can actually produce. The proposed systems start by get LDR panorama image from multiple LDR images using SIFT features technology and then convert this LDR panorama image to the HDR panorama image using inverted local patterns. The results in this paper explained that the HDR panorama images that resulting from the proposed method is more realistic image and appears as it is a real panorama environment.
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SHIMAMOTO, Masahito, Yusuke KAMEDA, and Takayuki HAMAMOTO. "HDR Imaging Based on Image Interpolation and Motion Blur Suppression in Multiple-Exposure-Time Image Sensor." IEICE Transactions on Information and Systems E103.D, no. 10 (October 1, 2020): 2067–71. http://dx.doi.org/10.1587/transinf.2020pcl0001.

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13

See, Zi Siang, Lizbeth Goodman, Craig Hight, Mohd Shahrizal Sunar, Arindam Dey, Yen Kaow Ng, and Mark Billinghurst. "Creating high fidelity 360° virtual reality with high dynamic range spherical panorama images." Virtual Creativity 9, no. 1 (December 1, 2019): 73–109. http://dx.doi.org/10.1386/vcr_00006_1.

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Abstract This research explores the development of a novel method and apparatus for creating spherical panoramas enhanced with high dynamic range (HDR) for high fidelity Virtual Reality 360 degree (VR360) user experiences. A VR360 interactive panorama presentation using spherical panoramas can provide virtual interactivity and wider viewing coverage; with three degrees of freedom, users can look around in multiple directions within the VR360 experiences, gaining the sense of being in control of their own engagement. This degree of freedom is facilitated by the use of mobile displays or head-mount-devices. However, in terms of image reproduction, the exposure range can be a major difficulty in reproducing a high contrast real-world scene. Imaging variables caused by difficulties and obstacles can occur during the production process of spherical panorama facilitated with HDR. This may result in inaccurate image reproduction for location-based subjects, which will in turn result in a poor VR360 user experience. In this article we describe a HDR spherical panorama reproduction approach (workflow and best practice) which can shorten the production processes, and reduce imaging variables, and technical obstacles and issues to a minimum. This leads to improved photographic image reproduction with fewer visual abnormalities for VR360 experiences, which can be adaptable into a wide range of interactive design applications. We describe the process in detail and also report on a user study that shows the proposed approach creates images which viewers prefer, on the whole, to those created using more complicated HDR methods, or to those created without the use of HDR at all.
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Hafstad, A., L. E. Aaro, A. Engeland, A. Andersen, F. Langmark, and B. Stray-Pedersen. "Provocative appeals in anti-smoking mass media campaigns targeting adolescents--the accumulated effect of multiple exposures." Health Education Research 12, no. 2 (June 1, 1997): 227–36. http://dx.doi.org/10.1093/her/12.2.227.

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15

Distler, Allison, Jason B. Brayer, Mark Meads, Eva Sahakian, John Joseph Powers, Melissa Alsina, Taiga Nishihori, et al. "HDAC11 as a candidate therapeutic target in multiple myeloma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 8029. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.8029.

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8029 Background: Histone deacetylase (HDAC) inhibitors (HDI) have a therapeutic niche in multiple myeloma (MM) due to their ability to salvage proteasome inhibitor and immunomodulatory drug responsiveness in refractory patients, thus raising interest in this therapeutic class. Selective HDI may further improve therapeutic efficacy. Methods: B cell lymphopoiesis was evaluated using Tg-HDAC11-eGFP mice expressing eGFP regulated by the HDAC11 promoter and congenic mouse strains deficient in HDAC11 expression globally (B6.HDAC11-/-) or targeted to the B cell lineage (CD19Cre.HDAC11-/-). Molecular and pharmacologic means were used to impair HDAC11 in established MM cell lines. Viability was measured by activated caspase-3, Annexin/PI (A/PI) staining, and CCK-8 viability assay. Subcellular localization changes induced by HDI and identification of the novel binding partner IRF4 were assessed by proximity ligation assay (PLA). Results: Profound eGFP increases in PC of Tg-HDAC11-eGFP mice suggest HDAC11 influences late stage B cell development. In addition, HDAC11 deficiency results in dramatically reduced PC in the bone marrow and periphery. PC depletion in CD19Cre.HDAC11-/-mice suggests activity inherent in B cells rather than via externally derived signals. Quisinostat (QS), an HDI with enhanced HDAC11 selectivity, showed dose-dependent cytotoxicity in 10 MM cell lines (EC50 1-10nM). This activity was synergistic with bortezomib (BTZ) and carfilzomib (CFZ) in RPMI-8226 cells, while synergism was amplified in the BTZ-resistant RPMI-8226-B25 cell line. Exposure of RPMI-8226 cells to QS decreased detection of nuclear, but not cytosolic, HDAC11. Targeted siRNA–mediated silencing of HDAC11 in RPMI-8226 cells activated caspase-3 and reduced viability by A/PI staining. PLA of MM cell lines showed a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, unmasking a potential mechanism for HDAC11-induced cytotoxicity in MM. This interaction was disrupted by QS. Conclusions: We show that HDAC11 inhibition reduces MM cell survival in vitro. Furthermore, we identify IRF4 as a binding partner for HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and MM survival.
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Evans, W. Douglas, Elizabeth L. Andrade, Nicole Barrett, Jeremy Snider, Sean Cleary, and Mark Edberg. "Outcomes of the Adelante community social marketing campaign for Latino youth." Health Education Research 34, no. 5 (May 18, 2019): 471–82. http://dx.doi.org/10.1093/her/cyz016.

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Abstract The authors designed and evaluated an innovative, branded campaign called ‘Adelante’ to promote positive youth development (PYD) and reduce risk behaviors among Latino youth near Washington, DC. Repeated cross-sectional surveys were conducted in the intervention and a comparison community to evaluate campaign exposure and changes in PYD outcomes. The sample consisted of 1549 Latino and immigrant adolescents surveyed at three time points in intervention and comparison communities. A social marketing campaign was implemented using outdoor advertising, Web, video and social media channels to promote PYD and health outcomes over a 1-year period from 2015 to 2016. Measures included media use; self-reported exposure to campaign promotions; Adelante message receptivity; validated PYD scales; substance use, sexual risk taking, violence-related knowledge, attitudes, beliefs, intentions and risk behavior. Outcomes were regressed first on campaign exposure to examine dose–response effects of the Adelante campaign over time. Second, we compared outcomes between the Adelante and comparison communities. We observed a positive effect of self-reported exposure on multiple outcomes, including improvements in pro-violence and sexual risk outcomes and lower pro-violence attitudes and lower risky attitudes toward sex. Adelante was effective in improving youth risk outcomes and offers a promising model for future health promotion with Latino and immigrant populations.
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Ledda, Patrick. "Product Review: High Dynamic Range Displays." Presence: Teleoperators and Virtual Environments 16, no. 1 (February 1, 2007): 119–22. http://dx.doi.org/10.1162/pres.16.1.119.

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In the natural world, the human eye is confronted with a wide range of colors and luminances. A surface lit by moonlight might have a luminance level of around 10−3 cd/m2, while surfaces lit during a sunny day could reach values larger than 105 cd/m2. A good quality CRT (cathode ray tube) or LCD (liquid crystal display) monitor is only able to achieve a maximum luminance of around 200 to 300 cd/m2 and a contrast ratio of not more than two orders of magnitude. In this context the contrast ratio or dynamic range is defined as the ratio of the highest to the lowest luminance. We call high dynamic range (HDR) images, those images (or scenes) in which the contrast ratio is larger than what a display can reproduce. In practice, any scene that contains some sort of light source and shadows is HDR. The main problem with HDR images is that they cannot be displayed, therefore although methods to create them do exist (by taking multiple photographs at different exposure times or using computer graphics 3D software for example) it is not possible to see both bright and dark areas simultaneously. (See Figure 1.) There is data that suggests that our eyes can see detail at any given adaptation level within a contrast of 10,000:1 between the brightest and darkest regions of a scene. Therefore an ideal display should be able to reproduce this range. In this review, we present two high dynamic range displays developed by Brightside Technologies (formerly Sunnybrook Technologies) which are capable, for the first time, of linearly displaying high contrast images. These displays are of great use for both researchers in the vision/graphics/VR/medical fields as well as professionals in the VFX/gaming/architectural industry.
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Gonçalves, Michele Martins, Cláudio Rodrigues Leles, and Maria do Carmo Matias Freire. "Associations between Caries among Children and Household Sugar Procurement, Exposure to Fluoridated Water and Socioeconomic Indicators in the Brazilian Capital Cities." International Journal of Dentistry 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/492790.

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The objective of this ecological study was to investigate the association between caries experience in 5- and 12-year-old Brazilian children in 2010 and household sugar procurement in 2003 and the effects of exposure to water fluoridation and socioeconomic indicators. Sample units were all 27 Brazilian capital cities. Data were obtained from the National Surveys of Oral Health; the National Household Food Budget Survey; and the United Nations Program for Development. Data analysis included correlation coefficients, exploratory factor analysis, and linear regression. There were significant negative associations between caries experience and procurement of confectionery, fluoridated water, HDI, and per capita income. Procurement of confectionery and soft drinks was positively associated with HDI and per capita income. Exploratory factor analysis grouped the independent variables by reducing highly correlated variables into two uncorrelated component variables that explained 86.1% of total variance. The first component included income, HDI, water fluoridation, and procurement of confectionery, while the second included free sugar and procurement of soft drinks. Multiple regression analysis showed that caries is associated with the first component. Caries experience was associated with better socioeconomic indicators of a city and exposure to fluoridated water, which may affect the impact of sugars on the disease.
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Bengala, C., C. Zamagni, P. Pedrazzoli, P. Matteucci, A. Ballestrero, G. Da Prada, M. Martino, et al. "Cardiac tolerability of trastuzumab in metastatic breast cancer (MBC) patients previously treated with high-dose chemotherapy (HDC) with autologous hemopoietic support: Retrospective analysis from Gruppo Italiano Trapianto Midollo Osseo (GITMO) Solid Tumor Working Party." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10558. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10558.

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10558 Background: HER-2 overexpression is associated to a poor prognosis in high-risk and MBC patients treated with HDC. HER-2 status is also a predictive factor of response to trastuzumab: when trastuzumab is administered in combination with or sequentially to chemotherapy, a significant DFS and/or survival improvement has been observed in HER2+ early and MBC. Unfortunately, in both settings, trastuzumab was associated with an increased risk of cardiac dysfunctions (CD). Patients and Methods: In order to evaluate the cardiac safety of trastuzumab after HDC, we have reviewed the clinical charts of HER2-overexpressing MBC patients treated with HDC and trastuzumab at 11 centres of the GITMO group. Age, baseline LVEF, radiation therapy on cardiac area, exposure to anthracycline, single or multiple transplant, high-dose agents, trastuzumab treatment duration were recorded as potential risk factors. Cardiac dysfunction (CD) was defined as: 1) decline of LVEF ≥ 10% to below 50%, 2) decline of LVEF between 5 and 9% to below 50% with symptomatic (NYHA class III-IV) congestive heart failure (CHF), 3) any symptomatic CHF event. Results: Fifty-three patients treated between 1999 and 2005 have been included in the analysis. Median age was 47 years (range 29–66). Median interval between HDC and trastuzumab was 6 months. Median LVEF at baseline was 60.5%; at the end of trastuzumab (data available for 28 patients only) it was 55% (p = 0.01). Five out of the 28 (17.9%) pts experienced CD. Two out of 53 (3.8%) pts developed a symptomatic (NYHA class III) CHF. Age ≥ 50 years was the only factor significantly associated with CD. However age ≥ 50 years and multiple transplant procedure were associated with a significant decline of LVEF (p: 0.02). Conclusion: The incidence of CD is not superior to that reported with trastuzumab after standard chemotherapy. However pts with age ≥ 50 years or receiving multiple course of HDC, should be considered at risk for CD. No significant financial relationships to disclose.
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Chen, Sung-Wei, Anne Peasey, Denes Stefler, Sofia Malyutina, Andrzej Pajak, Ruzena Kubinova, Jen-Hui Chan, Martin Bobak, and Hynek Pikhart. "Effort–reward imbalance at work, over-commitment personality and diet quality in Central and Eastern European populations." British Journal of Nutrition 115, no. 7 (February 12, 2016): 1254–64. http://dx.doi.org/10.1017/s0007114515005516.

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AbstractThe aims of this study were to investigate the associations between work stress defined by the effort–reward imbalance (ERI) model and diet quality and to examine the potential role of over-commitment (OC) personality in ERI–diet relationships. A cross-sectional study was conducted in random population samples of 6340 men and 5792 women (age 45–69 years) from the Czech Republic, Russia and Poland. Dietary data were collected using FFQ. The healthy diet indicator (HDI) was constructed using eight nutrient/food intakes (HDI components) to reflect the adherence to WHO dietary guideline. The extent of imbalance between effort and reward was measured by the effort:reward (ER) ratio; the effort score was the numerator and the reward score was multiplied by a factor adjusting for unequal number of items in the denominator. Logistic regression and linear regression were used to assess the associations between exposures (ER ratio and OC) and outcomes (HDI components and HDI) after adjustment for confounders and mediators. The results showed that high ER ratio and high OC were significantly associated with unhealthy diet quality. For a 1-sd increase in the ER ratio, HDI was reduced by 0·030 and 0·033 sd in men and women, and for a 1-sd increase in OC, HDI was decreased by 0·036 and 0·032 sd in men and women, respectively. The modifying role of OC in ERI–diet relationships was non-significant. To improve diet quality at workplace, a multiple-level approach combining organisational intervention for work stress and individual intervention for vulnerable personality is recommended.
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Anyanwu, Ebere, Andrew W. Campbell, Aristo Vojdani, John E. Ehiri, and Akpan I. Akpan. "Biochemical Changes in the Serum of Patients with Chronic Toxigenic Mold Exposures: A Risk Factor for Multiple Renal Dysfunctions." Scientific World JOURNAL 3 (2003): 1058–64. http://dx.doi.org/10.1100/tsw.2003.92.

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This paper analyzes and presents the biochemical abnormalities in the sera of patients presenting with chronic mycosis in order to investigate the relationship with the risks of multiple renal disorders. The study population (n = 10) consisted of six females and four males (mean age 36.3 years) exposed by toxic molds in their homes and offices for an average of 2.8 years. The control group comprised ten people, five males and five females (mean age 35.9 years) without any known exposures to toxic molds. Blood samples were obtained from both the patients and the controls and were processed using specific biochemical methods that included enzyme-linked immunoabsorbent assay (ELISA). There were biochemical abnormal concentrations in creatinine, uric acid, phosphorus, alkaline phosphotase, cholesterol, HDH, SGOT/AST, segmented neutrophils, lymphocytes, total T3, IgG and IgA immunoglobulins with significant differences between patients and controls. These abnormalities were consistent with multiple renal disorders. The major complaints of the mycosis patients were headaches, pulmonary symptoms, allergic reactions, memory loss, skin rashes, blurred vision symptoms, fatigue, and runny nose. These findings were depictive of a strong association of chronic mycosis with abnormal renal indicators. It was concluded that, although this research was a pilot investigation, based on the overall results, people exposed to chronic indoor environmental toxic molds were at risk of multiple renal complications.
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Ignotti, Eliane, Joaquim Gonçalves Valente, Karla Maria Longo, Saulo Ribeiro Freitas, Sandra de Souza Hacon, and Paulo Artaxo Netto. "Impact on human health of particulate matter emitted from burnings in the Brazilian Amazon region." Revista de Saúde Pública 44, no. 1 (February 2010): 121–30. http://dx.doi.org/10.1590/s0034-89102010000100013.

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OBJECTIVE: To analyze the impact on human health of exposure to particulate matter emitted from burnings in the Brazilian Amazon region. METHODS: This was an ecological study using an environmental exposure indicator presented as the percentage of annual hours (AH%) of PM2.5 above 80 μg/m3. The outcome variables were the rates of hospitalization due to respiratory disease among children, the elderly and the intermediate age group, and due to childbirth. Data were obtained from the National Space Research Institute and the Ministry of Health for all of the microregions of the Brazilian Amazon region, for the years 2004 and 2005. Multiple regression models for the outcome variables in relation to the predictive variable AH% of PM2.5 above 80 μg/m3 were analyzed. The Human Development Index (HDI) and mean number of complete blood counts per 100 inhabitants in the Brazilian Amazon region were the control variables in the regression analyses. RESULTS: The association of the exposure indicator (AH%) was higher for the elderly than for other age groups (β = 0.10). For each 1% increase in the exposure indicator there was an increase of 8% in child hospitalization, 10% in hospitalization of the elderly, and 5% for the intermediate age group, even after controlling for HDI and mean number of complete blood counts. No association was found between the AH% and hospitalization due to childbirth. CONCLUSIONS: The indicator of atmospheric pollution showed an association with occurrences of respiratory diseases in the Brazilian Amazon region, especially in the more vulnerable age groups. This indicator may be used to assess the effects of forest burning on human health.
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Johnson, David C., Sophie L. Corthals, Brian A. Walker, Fiona M. Ross, Walter M. Gregory, Nicholas J. Dickens, Henk M. Lokhorst, et al. "Genetic Factors Underlying the Risk of Thalidomide-Related Neuropathy in Patients With Multiple Myeloma." Journal of Clinical Oncology 29, no. 7 (March 1, 2011): 797–804. http://dx.doi.org/10.1200/jco.2010.28.0792.

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Purpose To indentify genetic variation that can modulate and predict the risk of developing thalidomide-related peripheral neuropathy (TrPN). Patients and Methods We analyzed DNA from 1,495 patients with multiple myeloma. Using a custom-built single nucleotide polymorphism (SNP) array, we tested the association of TrPN with 3,404 SNPs. The SNPs were selected in predicted functional regions within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and adverse effects associated with myeloma and its therapy. Patient cases and controls were derived from two large clinical trials that compared thalidomide with conventional-based treatment in myeloma patients (Medical Research Council Myeloma-IX and HOVON-50/GMMG-HD3). Results We report TrPN associations with SNPs—ABCA1 (rs363717), ICAM1 (rs1799969), PPARD (rs2076169), SERPINB2 (rs6103), and SLC12A6 (rs7164902)—where we show cross validation of the associations in both trials. To investigate whether TrPN SNP associations were related to exposure to thalidomide only or general drug-related peripheral neuropathy, we performed a second analysis on patients treated with vincristine. We report SNPs associated with vincristine neuropathy, with a seemingly distinct underlying genetic mechanism. Conclusion Our results are consistent with the hypothesis that an individual's risk of developing a peripheral neuropathy after thalidomide treatment can be mediated by polymorphisms in genes governing repair mechanisms and inflammation in the peripheral nervous system. These findings will contribute to the development of future neuroprotective strategies with thalidomide therapy and the better use of this important compound.
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Diehl, Sean A., Benjamin McElvany, Rajkumar Noubade, Nathan Seeberger, Brock Harding, Karen Spach, and Cory Teuscher. "G Proteins Gαi1/3Are Critical Targets for Bordetella pertussis Toxin-Induced Vasoactive Amine Sensitization." Infection and Immunity 82, no. 2 (December 9, 2013): 773–82. http://dx.doi.org/10.1128/iai.00971-13.

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ABSTRACTPertussis toxin (PTX) is an AB5-type exotoxin produced by the bacteriumBordetella pertussis, the causative agent of whooping cough.In vivointoxication with PTX elicits a variety of immunologic and inflammatory responses, including vasoactive amine sensitization (VAAS) to histamine (HA), serotonin (5-HT), and bradykinin (BDK). Previously, by using a forward genetic approach, we identified the HA H1receptor (Hrh1/H1R) as the gene in mice that controls differential susceptibility toB. pertussisPTX-induced HA sensitization (Bphs). Here we show, by using inbred strains of mice, F1hybrids, and segregating populations, that, unlike Bphs, PTX-induced 5-HT sensitivity (Bpss) and BDK sensitivity (Bpbs) are recessive traits and are separately controlled by multiple loci unlinked to 5-HT and BDK receptors, respectively. Furthermore, we found that PTX sensitizes mice to HA independently of Toll-like receptor 4, a purported receptor for PTX, and that the VAAS properties of PTX are not dependent upon endothelial caveolae or endothelial nitric oxide synthase. Finally, by using mice deficient in individual Gαi/oG-protein subunits, we demonstrate that Gαi1and Gαi3are the criticalin vivotargets of ADP-ribosylation underlying VAAS elicited by PTX exposure.
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Dimopoulos, Meletios A., V. L. Souliotis, A. Anagnostopoulos, A. Pouli, I. Baltadakis, E. Terpos, and Petros P. Sfikakis. "Measurement of Individual p53-Specific Damage Formation and Repair Following In Vitro Exposure of Peripheral Mononuclear Cells to Melphalan May Predict Clinical Outcome in Patients with Multiple Myeloma (MM) Subsequently Treated with High Dose Melphalan (HDM) and Autologous Blood Stem Cell Transplantation (ASCT)." Blood 106, no. 11 (November 16, 2005): 1167. http://dx.doi.org/10.1182/blood.v106.11.1167.1167.

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Abstract Introduction: Melphalan reacts extensively with cellular DNA. DNA monoadducts (MA) and interstrand cross-links (ICL) are the main events occurring after drug exposure. Subsequently, complex pathways contribute to repair of DNA lesions. We have previously showed that individual repairing capacity in p53 gene in vivo varied up to 16-fold among pts with MM receiving HDM, while increased DNA damage and slower repairing capacity correlated with improved clinical outcome (Dimopoulos et al, JCO 2005). We examine here if measurement of gene-specific DNA damage formation and repair after in vitro exposure of peripheral blood lymphocytes (PBL) to melphalan correlates with in vivo DNA damage and repair after exposure to HDM and if in vitro findings correlate with subsequent clinical outcome. Methods: Gene-specific MA and ICL formation and repair in the p53 gene were measured in PBL from MM pts, candidates for HDM (200mg/m2) and ASCT following in vitro exposure to 10 μg/ml melphalan for 1 h at 37°C. Measurements were performed 0, 2, 8 and 24 hours after in vitro exposure to melphalan. The same measurements were performed in vivo at 0, 2, 8 and 24 hours after treatment with HDM as previously described. Individual amounts of each type of DNA adducts over time (0–24h) were assessed by the area under the curve (AUC) during the whole experiment. Response after HDM was assessed according to the EBMT criteria. Measurements of DNA adducts after in vivo and in vitro treatment were correlated by the correlation-coefficient method. Results: So far, in 25 pts in vitro measurements have been performed and in 15 pts in vivo measurements and correlations with clinical outcome were made as well. One pt was treated in relapse, 3 patients had primary refractory disease and 11 were in remission. Individual kinetics of melphalan-induced DNA damage formation and repair varied remarkably among patients both for the in vivo and in vitro measurements. A strong correlation between in vivo and in vitro measurements was found (p≤0.02 for all measurements). Patients were separated into 2 groups. Responders i.e. patients who achieved CR or PR (n=10) after HDM and non responders i.e. pts who were rated as SD or PD (n=5). A significant correlation of clinical response with p53 gene-specific damage formation and repair was found in both in vitro and in vivo data. AUC (adducts/106 nucleotides x h) Total adducts (mean) Interstrand crosslinks (mean) Monoadducts (mean) Responders 919 +/− 215 303,9 +/− 108 616 +/− 154 In vitro Non responders 495 +/− 220 161,3 +/− 80,8 336 +/− 154 p-value 0,003 0,02 0,006 Responders 257 +/− 76 29,4 +/− 8,5 229 +/− 68 In vivo Non responders 122 +/− 91 13,8 +/− 4,6 112,8 +/− 82 p-value 0,009 0,002 0,01 Conclusion: Our results suggests that individuals with slower repairing capacity of the in vitro melphalan-induced p53 damage in peripheral blood lymphocytes have improved clinical outcome following subsequent treatment with HDM. We believe that our ongoing study may help select patients with MM who are more likely to benefit from HDM.
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26

Miguel, Jesús F. San, Paul G. Richardson, Robert Z. Orlowski, Hartmut Goldschmidt, Deyanira Corzo, Carol Satler, Dixie-Lee Esseltine, et al. "Risk of Second Primary Malignancies (SPMs) Following Bortezomib (Btz)-Based Therapy: Analysis of Four Phase 3 Randomized Controlled Trials in Previously Untreated or Relapsed Multiple Myeloma (MM)." Blood 118, no. 21 (November 18, 2011): 2933. http://dx.doi.org/10.1182/blood.v118.21.2933.2933.

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Abstract Abstract 2933 Background: MM patients have a significantly increased risk of developing certain SPMs subsequent to their initial diagnosis, including a 3.49-fold increased risk of leukemia and, specifically, an 8.32-fold increased risk of acute non-lymphocytic leukemia (but no overall increased risk of solid tumor SPMs; Surveillance, Epidemiology and End Results [SEER] data 1973–2000). The relative SPM risk increases with age and time after initial diagnosis; the risk of leukemia rises from a 1.22-fold increase within 1 year after diagnosis to 3.12-fold, 7.01-fold, and 5.45-fold increases at 1–4, 5–9, and ≥10 years, respectively. An elevated risk of SPMs may be particularly associated with the use of specific therapeutic agents, including conventional or high-dose cytotoxic chemotherapy. Here we report an analysis of data from four phase 3, randomized, controlled trials of Btz alone or in combination to determine whether Btz treatment is associated with an increased SPM risk. Methods: Data were reviewed from: 1) the APEX study of Btz versus high-dose dexamethasone (Dex), and 2) the MMY-3001 study of Btz plus pegylated liposomal doxorubicin (PLD) versus Btz in patients with relapsed or refractory MM after 1–3 prior therapies; 3) the VISTA study of Btz plus melphalan-prednisone (VMP) versus MP in previously untreated transplant-ineligible patients; and 4) the HOVON65/GMMG-HD4 study of Btz, doxorubicin, and Dex (PAD) induction plus Btz maintenance post-transplant versus vincristine, doxorubicin, and Dex (VAD) induction plus thalidomide (Thal) maintenance in previously untreated transplant-eligible patients. Planned duration of Btz therapy was 39 weeks in APEX, 24 weeks in MMY-3001, 54 weeks in VISTA, and 9 weeks induction plus 2 years of maintenance in HOVON65/GMMG-HD4. For APEX, MMY-3001, and VISTA, clinical trial databases were reviewed for events within the MedDRA system organ class of ‘neoplasms’, and new malignancies developing during or after treatment were recorded (excluding non-melanomatous skin cancers and in situ malignancies). In addition, for VISTA, data were obtained from an SPM survey after a median follow-up of 5 years. For HOVON65/GMMG-HD4, data were prospectively collected; median follow-up was 42 months. The incidence rate (IR) of SPMs was expressed as the number per 100 patient-years (pt-yrs). Results: The risk of SPMs with Btz-based therapy appeared uniformly low across all four phase 3 studies in different MM patient populations (Table). A total of 25 SPMs were seen in 1718 Btz-treated patients, including three cases of acute myeloid leukemia/myelodysplastic syndromes, one B-cell malignancy, and one case of cutaneous T-cell lymphoma (in a patient with substantial prior alkylating agent exposure for treatment of MM), plus 20 reports of solid tumors (reflecting the higher overall incidence of these tumors). The IR ranged from 0 in the single-agent Btz arm of MMY-3001 to 1.66 with VMP in VISTA, with an IR of 0.88 in APEX and 0.3 in the PAD arm of HOVON65/GMMG-HD4; median age of Btz-treated patients was highest in VISTA, at 71 years. Overall rates (%) also appeared higher in VISTA, probably due to the longer follow-up and older population, plus the potential effects of concomitant chemotherapy. In the three studies with non-Btz control arms, the IR did not appear to be increased with Btz-based therapy versus the control arm, and across all Btz-containing arms in the four studies, the IRs for hematologic malignancies and solid tumors were consistent with SEER estimates (2004–2008 data) of the overall incidence of malignancies in the US population, of 1.1, 1.9, and 2.4 per 100 pt-yrs in individuals aged 55–64, 65–74, and 75–84 years, respectively. Conclusions: Btz-based therapy for MM does not appear to be associated with an increased risk of either hematologic or solid tumor SPMs, with IRs consistent with SEER data for IRs in the overall US population. Disclosures: San Miguel: Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Richardson:Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy. Orlowski:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Onyx: Consultancy; Cephalon: Consultancy; Centocor: Consultancy; Celgene: Consultancy, Research Funding. Goldschmidt:Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Satler:Millennium Pharmaceuticals, Inc.: Employment. Esseltine:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership; Johnson & Johnson: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Ponsillo:Millennium Pharmaceuticals, Inc.: Employment. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. King:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Desai:Janssen Global Services: Employment; Johnson & Johnson: Equity Ownership. Lutska:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Gifkins:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Liu:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership.
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27

Sun, Shao, Qiang Zhang, Yuanxin Xu, and Ruyue Yuan. "Integrated Assessments of Meteorological Hazards across the Qinghai-Tibet Plateau of China." Sustainability 13, no. 18 (September 17, 2021): 10402. http://dx.doi.org/10.3390/su131810402.

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Recent decades have witnessed accelerated climate changes across the Qinghai-Tibet Plateau (QTP) and elevated socioeconomic exposure to meteorological hazards. The QTP is called the “the third pole”, exerting remarkable impact on environmental changes in its surrounding regions. While few reports are available for addressing multi-hazard risks over the QTP, we develop an integrated indicator system involving multiple meteorological hazards, i.e., droughts, rainstorms, snowstorms and hailstorms, investigating the spatiotemporal patterns of major hazards over the QTP. The hazard zones of droughts and rainstorms are identified in the southern Gangdise Mountains, the South Tibet Valley, the eastern Nyenchen-Tanglha Mountains, the Hengduan Mountains and West Sichuan Basin. Snowstorm hazard zones distribute in the Himalayas, the Bayan Har Mountains and the central Nyenchen-Tanglha Mountains, while hailstorm hazard zones cluster in central part of the QTP. Since the 21st century, intensified rainstorms are detectable in the densely populated cities of Xining and Lhasa and their adjacent areas, while amplified droughts are observed in grain production areas of the South Tibet Valley and the Hengduan Mountains. Snowstorm hazards show large interannual variations and an increase in pastoral areas, although the overall trend is declining slightly. The frequency of hailstorms gradually decreases in human settlements due to thermal and landscape effects. Mapping meteorological hazards regionalization could help to understand climate risks in the QTP, and provide scientific reference for human adaptation to climate changes in highly sensitive areas.
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28

Gu, Dongmin, Hua Wang, Zhiqiang Wang, Richard E. Davis, Shengli Cai, Takahiko Seki, Archie Tse, and Robert Z. Orlowski. "The Novel Human Double Minute (HDM)-2 Inhibitor DS-5272 Is Active Both Alone, and In Combination With Other Novel Agents, Against Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 1927. http://dx.doi.org/10.1182/blood.v122.21.1927.1927.

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Abstract Background The ubiquitin-proteasome pathway is now a validated target for myeloma therapy given the regulatory approvals of proteasome inhibitors such as bortezomib and carfilzomib. Another logical set of targets are the E3 ligases, whose role is to facilitate the protein poly-ubiquitination typically needed for recognition by the constitutive or immunoproteasome prior to proteolysis. One of the more attractive such targets is HDM-2, the E3 ligase best known for its role in turnover of the p53 tumor suppressor, in part because p53 deletion or mutation is less common in myeloma than in solid tumors, and because it has been possible to develop agents targeting the HDM-2 p53 binding pocket. Methods Activity of the specific HDM-2 inhibitor DS-5272 (Daiichi-Sankyo) was evaluated using a panel of p53 wild-type (wt) and mutant (mut) myeloma cell lines and also against primary patient samples. Studies were performed with DS-5272 both alone, and also in combination regimens with novel agents. Tetrazolium dye-based assays were employed to determine cell viability, Annexin V staining was used to examine apoptosis, and quantitative PCR and Western blotting were used to study selected transcripts and gene products, respectively. This study was supported in part by the M. D. Anderson Cancer Center SPORE in Multiple Myeloma. Results DS-5272 induced potent cytotoxicity in wt p53 MM1.S, H929, and MOLP-8 myeloma cell lines, with a median inhibitory concentration (IC50) in the single micromolar range, which was reproduced in studies of primary CD138+ plasma cells but not CD138- cells from myeloma patients. This cytotoxicity was both time- and concentration-dependent, and DS-5272 was more potent than the prototypical HDM-2 inhibitors, Nutlin-3a and MI-219. A dependence of DS-5272 activity on wt p53 was demonstrated by the much lower IC50 in the wt p53 than mut p53 cell lines, and the finding that suppression of p53 with a shRNA, as well as mutation of p53 with a sequence-specific zinc finger nuclease, significantly increased the IC50. Notably, DS-5272 remained active in the presence of conditioned media from stromal cells, or key myeloma cytokines such as IL-6. The reduced viability after exposure to DS-5272 was due at least in part to activation of type I cell death, as determined by increased staining for Annexin V, activation of caspases 9 and 3, and cleavage of PARP. Other downstream effects included induction of transcription of p21, Bax, HDM-2, NOXA, and PUMA. These proteins, as well as p27 and p53 were induced, while the abundance of Survivin, CHK1, Aurora A and B, PLK1, and KIF11 was reduced. Consistent with these latter effects, DS-5272 induced some accumulation of cells at the G2/M phase, and the appearance of cells with a disordered spindle. Suppression of KIF11 (kinesin spindle protein (KSP; Eg5)), which is responsible for centromere separation and bipolar spindle formation, seemed to occur through the binding of p21 to the cell cycle genes homology region (CHR) within the KIF11 promoter. Finally, combinations of DS-5272 with the specific KIF11 inhibitor Ispinesib produced enhanced G2/M arrest, as well as a synergistic reduction in cell viability with increased levels of apoptosis. Conclusion DS-5272 is a potent and novel agent with activity against multiple myeloma, and is active both alone and in rationally designed combination regimens with other drugs. These findings provide a rationale for the clinical translation of HDM-2 inhibitors as monotherapy, and possibly with other agents such as the KSP inhibitor ARRY-520, which is also active against myeloma, for patients with wt p53 relapsed and/or refractory myeloma. Disclosures: Cai: Daiichi-Sankyo Pharma Development: Employment, Equity Ownership. Seki:Daiichi Sankyo Co., Ltd.: Employment, Equity Ownership. Tse:Daiichi-Sankyo Pharma Development: Employment, Equity Ownership.
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29

Mostofa, AGM, Allison Distler, Mark B. Meads, Eva Sahakian, John J. Powers, Tuan Nguyen, Melissa Alsina, et al. "Functional Analysis of HDAC11 in Plasma Cell Development and Multiple Myeloma Survival." Blood 132, Supplement 1 (November 29, 2018): 3223. http://dx.doi.org/10.1182/blood-2018-99-119119.

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Abstract Background: Histone deacetylases (HDACs) are potential novel therapeutic targets for multiple myeloma (MM) treatment. A pan-HDAC inhibitor (HDI) panobinostat was approved by the FDA in 2015 to treat relapsed/refractory MM patients, and several other HDIs are currently in different phases of clinical trials. However, unfavorable side-effects of the non-selective HDIs necessitate further dissection of the roles of individual HDAC isoforms to best target plasma cell malignancies with minimal toxicity. HDAC11 was recently found to regulate function in key immune cell populations including regulatory T cells, effector T cells, neutrophils, and myeloid-derived suppressor cells (MDSC). Though HDAC11 expression is confirmed in B cells and plasma cells, its functions in these cells remain largely unknown. In this study, we attempted a functional analysis of HDAC11 in plasma cell development along with its pro-tumorigenic function in MM cells. Methods: Mouse models, including a transgenic mouse strain expressing eGFP under the regulation of the HDAC11 promoter (Tg-HDAC11-eGFP), and also an HDA11-deficient mouse (B6.HDAC11-/-) were studied to establish the importance of HDAC11 in plasma cell biology. Pharmacologic inhibition of HDAC11 in MM cell lines was accomplished by using elevenostat, a new HDAC11-selective inhibitor in comparison with pan-inhibitors quisinostat and panobinostat. Impact on viability in human-derived MM cell lines was assessed using the CCK-8 assay, while induction of cell death was measured via detection of activated Caspase-3 and annexin/propidium iodide staining by flow cytometry. Synergy studies were performed by following the Chou-Talalay method for drug combinations. Post-translational modifications and subcellular localization changes induced by HDIs exposure were assessed by western blotting of fractionated cell lysates, while immunoprecipitation and proximity ligation assays (in situ PLA) were used to identify a binding partner for HDAC11. Results: Studies in Tg-HDAC11-eGFP mice reveal that HDAC11 expression in B cell lymphopoiesis is minimally detectable prior to B cell activation but demonstrates strong induction upon maturation into a plasma cell. Consistent with this, plasma cell development is markedly impaired in the absence of HDAC11. The HDAC11-selective inhibitor elevenostat showed significant cytotoxic potential in different MM cell lines that express moderate to high level of HDAC11, with IC50 values ranging 0.6-2.0 µM. Consistently, MM cell lines expressing null/very low level of HDAC11 were insensitive to elevenostat. Moreover, combining elevenostat with proteasome inhibitors bortezomib (BTZ) and carfilzomib resulted in significant synergistic effects evident from combination index (CI) and dose-reduction index (DRI) values measured by CompuSyn software. Elevenostat was also able to re-sensitize BTZ-resistant sub-clones (e.g., RPMI-8226-B25, KAS-6-V10R, and ANBL6-V10R) to BTZ and exhibited superior synergistic effects. Furthermore, elevenostat-treated cells showed a time-dependent alteration in the subcellular localization of HDAC11. HDAC11 gradually disappeared from the nuclear fractions with simultaneous upregulation in cytoplasmic fractions; similar observations were made from pan HDIs (quisinostat and panobinostat) treatment. However, unlike pan HDIs, the elevenostat treatment caused global downregulation of HDAC11 in some MM cell lines at the later time points (72 or 96 hrs), suggesting differential effects of various HDIs. Inhibition of HDAC11 also caused downstream suppression of several pro-tumorigenic factors of MM cells including IRF4 and c-Myc. Additionally, a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, was identified by using PLA. HDAC11 dynamically interacts with IRF4 which can be induced by LPS stimulation and inhibited by HDIs, indicating the involvement of HDAC11 in the IRF4-mediated regulatory circuit. Conclusions: We observe that targeted inhibition of HDAC11 can impair MM cell survival and overcome acquired resistance to proteasome inhibitors. Furthermore, we identify IRF4 as a nuclear binding partner of HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and survival. Disclosures No relevant conflicts of interest to declare.
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30

Bakovic, Allison, Nishank Bhalla, Farhang Alem, Catherine Campbell, Weidong Zhou, and Aarthi Narayanan. "Inhibitors of Venezuelan Equine Encephalitis Virus Identified Based on Host Interaction Partners of Viral Non-Structural Protein 3." Viruses 13, no. 8 (August 3, 2021): 1533. http://dx.doi.org/10.3390/v13081533.

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Venezuelan equine encephalitis virus (VEEV) is a new world alphavirus and a category B select agent. Currently, no FDA-approved vaccines or therapeutics are available to treat VEEV exposure and resultant disease manifestations. The C-terminus of the VEEV non-structural protein 3 (nsP3) facilitates cell-specific and virus-specific host factor binding preferences among alphaviruses, thereby providing targets of interest when designing novel antiviral therapeutics. In this study, we utilized an overexpression construct encoding HA-tagged nsP3 to identify host proteins that interact with VEEV nsP3 by mass spectrometry. Bioinformatic analyses of the putative interactors identified 42 small molecules with the potential to inhibit the host interaction targets, and thus potentially inhibit VEEV. Three inhibitors, tomatidine, citalopram HBr, and Z-VEID-FMK, reduced replication of both the TC-83 strain and the Trinidad donkey (TrD) strain of VEEV by at least 10-fold in astrocytoma, astroglial, and microglial cells. Further, these inhibitors reduced replication of the related New World (NW) alphavirus Eastern equine encephalitis virus (EEEV) in multiple cell types, thus demonstrating broad-spectrum antiviral activity. Time-course assays revealed all three inhibitors reduced both infectious particle production and positive-sense RNA levels post-infection. Further evaluation of the putative host targets for the three inhibitors revealed an interaction of VEEV nsP3 with TFAP2A, but not eIF2S2. Mechanistic studies utilizing siRNA knockdowns demonstrated that eIF2S2, but not TFAP2A, supports both efficient TC-83 replication and genomic RNA synthesis, but not subgenomic RNA translation. Overall, this work reveals the composition of the VEEV nsP3 proteome and the potential to identify host-based, broad spectrum therapeutic approaches to treat new world alphavirus infections.
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31

Jones, Richard J., Dajun Yang, Nathalie Bruey-Sedano, and Robert Z. Orlowski. "Targeting the Human Double Minute (HDM)-2 p53 Ubiquitin Ligase as a Strategy Against Non-Hodgkin Lymphoma." Blood 110, no. 11 (November 16, 2007): 1374. http://dx.doi.org/10.1182/blood.v110.11.1374.1374.

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Abstract Background: The ubiquitin-proteasome pathway has been validated as a target for non-Hodgkin lymphoma (NHL) with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of an anti-apoptotic heat shock protein response, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One such attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule MI-63, an inhibitor of the HDM-2-p53 interaction, in both p53 wild-type and -mutant cell line models. Results: Treatment of wild-type p53 MCL, NHL, and acute lymphocytic leukemia (ALL) cell lines with MI-63 induced a dose- and time-dependent inhibition of proliferation, with an IC50 in the 1.0–5.0 μM range. This was associated with G1/S cell cycle arrest, and apoptosis mediated by caspases-3, 8 and 9. MI-63 induced accumulation and phosphorylation of p53 at serine 15 and 37, and also enhanced HDM-2 levels. Multiple p53 target genes were induced, including p21Cip1 and p53-upregulated modulator of apoptosis (PUMA), resulting in cleavage of poly-ADP-ribose-polymerase (PARP). MI-63 also decreased the levels of the ribonucleotide reductase subunit R2, and caused a corresponding increase in the R2p53 subunit. MI-63 also decreased the levels of E2F. Cell lines expressing certain p53 mutants were sensitive to the effects of MI-63, resulting in apoptosis. Cells without p53 expression were less sensitive to MI-63, but at higher drug concentrations proliferation was still inhibited, indicating a possible impact on HDM-2-mediated but p53-independent cell death pathways. Primary human umbilical cord vein endothelial cell growth was also inhibited and cells failed to recover after extended exposure to MI-63, whereas primary PBMC’s were unaffected by MI-63. Combinations of MI-63 with the molecularly targeted chemotherapy agents bortezomib and rapamycin were synergistic, with mean CI values of 0.88 and 0.6 respectively. The conventional chemotherapy agents doxorubicin and cisplatin were less effective at inducing synergism, with mean CI values of 1.06 and 0.9 respectively. Pretreatment of cells with MI-63 followed by chemotherapy was antagonistic with all agents used, while treatment with a chemotherapeutic first followed by MI-63 was additive to synergistic, indicating a sequence-dependent interaction. Conclusions: Inhibition of the HDM-2-p53 interaction is a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies, providing a rationale for translation of such agents into the clinic.
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Takezako, Naoki, Naohiro Sekiguchi, Akihisa Nagata, Tsuyoshi Hagino, Satoshi Noto, Kazuhiko Natori, and Akiyoshi Miwa. "Subcutaneous Injection Of Bortezomib, Combined With Doxorubicin and Dexamethasone (sPAD) Is Effective and Safety Induction Therapy For Untreated Multiple Myeloma Patients." Blood 122, no. 21 (November 15, 2013): 5391. http://dx.doi.org/10.1182/blood.v122.21.5391.5391.

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Abstract Background Bortezomib is the first generation proteasome inhibitor which is used as induction therapy for multiple myeloma (MM) patients. Recently, triplet therapies including bortezomib are recommended by several committees. Among various triplet therapies, PAD (bortezomib, doxorubicin, and dexamethasone), which was reported in the analysis of randomized phase III HOVON-65/ GMMG-HD4 trial, is an effective therapy. Complete response (CR), including near CR, was superior after PAD induction to VAD induction (15% vs. 31%; P < .001) (Sonneveld P et al.). However, peripheral neuropathy (PN) was observed in 37% of PAD induction arm (grade 3 or 4 Peripheral neuropathy (PN) was 24%). Recently, some investigators reported that subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile (Moreau P et al.). PN was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. Therefore, we performed a phase 2 PAD study using subcutaneous bortezomib (sPAD) in Japanese MM patients. Materials and Methods Eligible patients were aged 20 years and older from whom was obtained written informed consent. Between July 2011 and April 2013, 30 symptomatic MM patients were enrolled in this trial. They received bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11) by subcutaneous injection, oral dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12), and intravenous doxorubicin (20 mg/m2 on days 1 and 4), every 21 days as their induction regimen. Subcutaneous injections were administrated with reduced-concentration to 2.0mg/ml (3mg bortezomib reconstituted with 1.5ml normal saline). In addition, we studied a pharmacokinetics of bortezomib. Plasma samples were collected in cycle 1 on day 11. Bortezomib plasma concentrations were measured with a validated liquid chromatography. We compared this sPAD therapy with intravenous injection bortezomib dexamethasone (BD) therapy (N=40), as a historical control. Statistical analyses were done with Stata /MP (version 12.1). Results Patient's characteristics at inclusion did not differ between two groups. Overall response rate (VGPR or CR) of sPAD therapy was superior to BD therapy (77% vs. 30%; p<0.001). The CR rate was 2.5% in patients who were treated with BD and 30% in patients who were treated with sPAD (p=0.001). The median progression free survival (PFS) was 6 months for the BD therapy and 22 months for the sPAD therapy. Patients who were treated with sPAD had a significantly better PFS (p<0.001). Median overall survival (OS) was not reached at 24 months in sPAD therapy and 23 months for BD therapy. Patients who were treated with sPAD had a significantly better OS (p=0.0251). Grade 3 or worse PN (5% vs. 28%; p=0.040) was significantly less common with sPAD than BD. Subcutaneous administration was locally well tolerated. Eight patients enrolled in the pharmacokinetic study. Table 1 shows bortezomib concentration profile after subcutaneous administration on day 11, cycle 1. Mean maximum plasma concentration of bortezomib (Cmax) was lower than previously reported level (Cmax = 12.27 ng/mL (7.41-19.40)). However, mean bortezomib systemic exposure (AUClast) was similar to previous report (AUClast = 156.8 ngxh/mL (85.0-240.0)). Conclusion sPAD therapy is promising induction therapy for untreated MM patients because of efficacy and safety. Furthermore, reduced bortezomib-concentration subcutaneous administration may help to reduce PN. Further study might be warranted. Disclosures: No relevant conflicts of interest to declare.
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Yovogan, Boulais, Arthur Sovi, Gil G. Padonou, Constantin J. Adoha, Bruno Akinro, Saïd Chitou, Manfred Accrombessi, et al. "Pre-intervention characteristics of the mosquito species in Benin in preparation for a randomized controlled trial assessing the efficacy of dual active-ingredient long-lasting insecticidal nets for controlling insecticide-resistant malaria vectors." PLOS ONE 16, no. 5 (May 20, 2021): e0251742. http://dx.doi.org/10.1371/journal.pone.0251742.

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Background This study provides detailed characteristics of vector populations in preparation for a three-arm cluster randomized controlled trial (RCT) aiming to compare the community impact of dual active-ingredient (AI) long-lasting insecticidal nets (LLINs) that combine two novel insecticide classes–chlorfenapyr or pyriproxifen–with alpha-cypermethrin to improve the prevention of malaria transmitted by insecticide-resistant vectors compared to standard pyrethroid LLINs. Methods The study was carried out in 60 villages across Cove, Zangnanando and Ouinhi districts, southern Benin. Mosquito collections were performed using human landing catches (HLCs). After morphological identification, a sub-sample of Anopheles gambiae s.l. were dissected for parity, analyzed by PCR for species and presence of L1014F kdr mutation and by ELISA-CSP to identify Plasmodium falciparum sporozoite infection. WHO susceptibility tube tests were performed by exposing adult An. gambiae s.l., collected as larvae from each district, to 0.05% alphacypermethrin, 0.75% permethrin, 0.1% bendiocarb and 0.25% pirimiphos-methyl. Synergist assays were also conducted with exposure first to 4% PBO followed by alpha-cypermethrin. Results An. gambiae s.l. (n = 10807) was the main malaria vector complex found followed by Anopheles funestus s.l. (n = 397) and Anopheles nili (n = 82). An. gambiae s.l. was comprised of An. coluzzii (53.9%) and An. gambiae s.s. (46.1%), both displaying a frequency of the L1014F kdr mutation >80%. Although more than 80% of people slept under standard LLIN, human biting rate (HBR) in An. gambiae s.l. was higher indoors [26.5 bite/person/night (95% CI: 25.2–27.9)] than outdoors [18.5 b/p/n (95% CI: 17.4–19.6)], as were the trends for sporozoite rate (SR) [2.9% (95% CI: 1.7–4.8) vs 1.8% (95% CI: 0.6–3.8)] and entomological inoculation rate (EIR) [21.6 infected bites/person/month (95% CI: 20.4–22.8) vs 5.4 (95% CI: 4.8–6.0)]. Parous rate was 81.6% (95%CI: 75.4–88.4). An. gambiae s.l. was resistant to alpha-cypermethrin and permethrin but, fully susceptible to bendiocarb and pirimiphos-methyl. PBO pre-exposure followed by alpha-cypermethrin treatment induced a higher 24 hours mortality compared to alphacypermethrin alone but not exceeding 40%. Conclusions Despite a high usage of standard pyrethroid LLINs, the study area is characterized by intense malaria transmission. The main vectors An. coluzzii and An. gambiae s.s. were both highly resistant to pyrethroids and displayed multiple resistance mechanisms, L1014F kdr mutation and mixed function oxidases. These conditions of the study area make it an appropriate site to conduct the trial that aims to assess the effect of novel dual-AI LLINs on malaria transmitted by insecticide-resistant vectors.
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Jones, Richard Julian, and Robert Z. Orlowski. "Drug Resistance to the HDM-2 Inhibitors MI-63 and Nutlin Is Mediated by Point Mutations of p53, but Can Be Overcome with the p53 Targeting Agent RITA." Blood 118, no. 21 (November 18, 2011): 2726. http://dx.doi.org/10.1182/blood.v118.21.2726.2726.

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Abstract Abstract 2726 Background: The ubiquitin-proteasome pathway has been validated as a target for multiple myeloma (MM) and mantle cell lymphoma (MCL) by the demonstration of the effectiveness of the proteasome inhibitor bortezomib (BZB) in these malignancies. E3 ubiquitin ligases are involved in ubiquitination of a small subset of cellular proteins and play an integral part in regulation of turnover of cellular proteins. HDM-2 is the E3 ubiquitin ligase responsible for degradation and regulation of the p53 tumor suppressor, and HDM-2 inhibitors such as nutlin (NUT) and MI-63 stabilize p53 and enhance its pro-apoptotic effects in the absence of DNA damage. Methods: To evaluate the mechanisms through which wild type p53 MCL and MM cells could evade the therapeutic effects of HDM-2 inhibitors, we generated cell lines resistant to MI-63 and Nutlin. Resistant lines were generated by growing cells over a period of 3 months in increasing concentrations of either MI-63 or NUT until the cells were resistant to 10 mM of either agent. Results: H929 MM and Granta-519 MCL cells resistant to MI-63 (MI63R) were cross resistant to NUT, and NUT resistant (NUTR) cells displayed resistance to MI-63. Indeed, treatment of resistant cells with either MI-63 or NUT resulted in enhanced proliferation of these cells. MI-63R and NUTR cells showed enhanced resistance to both BZB and doxorubicin, whilst unexpectedly maintaining sensitivity to RITA (reactivation of p53 and induction of tumor cell apoptosis). Immunoblot analysis indicated increased levels of p53 in resistant cells at baseline and upon treatment with MI-63, NUT, or doxorubicin, but these treatments failed to induce p21 and HDM-2. Sequencing of genomic DNA from these cells for both HDM-2 and p53 genes indicated no alteration in the sequence of HDM-2. However, substitution mutations were found within p53 encompassing exons 4 through 8 for both NUTR and MI63R cells. When RITA was used in the resistant cells, an SG2 cell cycle arrest was seen at 48 hours post treatment. A time course analysis indicated that resistant cells treated with RITA displayed up-regulation of HDM-2, PUMA and NOXA from around 12 hours, with a corresponding induction of PARP cleavage from 48 to 72 hours. These data suggested RITA was able to restore wtp53 function resulting in induction of p53 transcriptional targets and thereby overcoming resistance to NUT and MI-63. The combination of either MI-63 or NUT with RITA demonstrated that simultaneous addition of the agents or pretreatment with RITA resulted in an enhancement of cell death over RITA alone. This result indicates that RITA restored the function of mutp53 within MI-63 and NUT resistant cells and thereby resensitized the cells to the effects of MI-63 or NUT. Conclusions: Chronic exposure of MM and MCL cells to HDM-2 inhibitors resulted in cross resistance to other inhibitors in the same class through mutation of p53 as the primary mechanism of resistance. HDM-2 inhibitor resistant cells did remain sensitive to the effects of RITA through restoration of p53 function, and restoring the sensitivity of such cells to agents that promote p53's pro apoptotic effects may be a rational strategy for translation to the clinic. Disclosures: No relevant conflicts of interest to declare.
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Laubach, Jacob P., Jesús F. San Miguel, Pieter Sonneveld, Robert Z. Orlowski, Philippe Moreau, Laura Rosiñol, Javid J. Moslehi, et al. "Quantifying The Risk Of Heart Failure Associated With Proteasome Inhibition: A Retrospective Analysis Of Heart Failure Reported In Phase 2 and Phase 3 Studies Of Bortezomib (Btz) In Multiple Myeloma (MM)." Blood 122, no. 21 (November 15, 2013): 3187. http://dx.doi.org/10.1182/blood.v122.21.3187.3187.

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Abstract Background Due to recent treatment advances, MM patients (pts) are living longer (Kumar et al, Blood 2008), underscoring the importance of patient quality of life and management of adverse events (AEs) related to MM therapy. MM pts are at risk of cardiac events due to age and disease-related factors, as well as cardiotoxicity from treatments including anthracyclines, proteasome inhibitors (PIs), and high-dose therapy. Both of the US FDA-approved PIs, Btz and carfilzomib, have been associated with cardiac events in MM pts, with cardiac toxicity and cardiac adverse reactions included under ‘Warnings and Precautions’ in the respective US labels. The development of Btz, a reversible boronate peptide PI, involved numerous large, controlled clinical trials, providing a benchmark for the expected incidence of heart failure with PIs. Here, we report a retrospective analysis of the risk of heart failure associated with Btz in phase 2 and 3 MM studies leading to regulatory approvals in the US and EU. Methods Study databases were retrospectively analyzed for AEs of grade ≥3 heart failure. In the relapsed/refractory setting, the following studies were included: the phase 2 SUMMIT trial (Btz ± dexamethasone; Richardson et al, NEJM 2003), and the phase 3 APEX (Btz vs dexamethasone; Richardson et al, NEJM 2005), MMY-3001 (Btz + liposomal doxorubicin vs Btz; Orlowski et al, J Clin Oncol 2007), and MMY-3021 (subcutaneous [SC] vs intravenous [IV] Btz; Moreau et al, Lancet Oncol 2011) trials. In the upfront setting, the phase 3 VISTA trial (Btz-melphalan-prednisone [VMP] vs MP; San Miguel et al, NEJM 2008) in transplant-ineligible pts and a pooled analysis of three phase 3 trials (IFM 2005-01, HOVON-65/GMMG-HD4, PETHEMA GEM2005MENOS65) of Btz-based vs non-Btz-based induction (N=779 vs 776; Sonneveld et al, IMW 2013) in transplant-eligible pts were included. Cardiac exclusion criteria typically included NYHA class III/IV (≥II in MMY-3001), myocardial infarction within 6 mos, and ECG evidence of acute ischemia. Heart function tests (primarily ECG) were incorporated in study designs. Heart failure events were analyzed and re-coded for consistency across studies, using standardized MedDRA (v4.0, 8.0, 8.1, 9.0, 9.1, and 10.0) query preferred terms with grouping of clinically related events. Results 2509 pts treated with Btz in the specified phase 2 and 3 trials and an additional 1445 pts treated with non-Btz-based therapies in the control arms of the phase 3 studies were included in this analysis. Pt characteristics and rates of grade ≥3 heart failure by study arm are shown in the table. Among all Btz-treated pts, the rate of grade ≥3 heart failure was 2.0%; the rate was 2.0% in newly diagnosed pts and 1.9% in relapsed and/or refractory pts. In the comparative studies (APEX, VISTA) and pooled pre-ASCT induction analysis, the overall rates across the Btz and non-Btz arms were 2.0% and 1.6%, respectively (p=0.41). Risk factors, including prior anthracycline exposure and history of cardiac complications, were balanced between Btz and non-Btz arms. Conclusions In this retrospective analysis of data from key phase 2 and 3 studies, Btz was associated with a low rate of grade ≥3 heart failure in both the newly diagnosed (2.0%) and relapsed and/or refractory (1.9%) settings. Importantly, across comparative studies, the rate was only marginally higher and not statistically different from the background rate in non-Btz comparator arms. Data from ongoing prospective and comparative studies are necessary to determine whether PIs – including Btz, carfilzomib, and PIs at earlier stages of clinical development – have different cardiotoxicity profiles. Disclosures: San Miguel: Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Sonneveld:Jansssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Moslehi:Alnylam: Consultancy; Novartis: Consultancy; Millennium: The Takeda Oncology Company: Consultancy; Forest Laboratories: Research Funding. Faber:Celgene: Consultancy, Honoraria; Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Voorhees:Acetylon: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Merck: Research Funding; Janssen: Research Funding; Prolexys Pharmaceuticals: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbott Laboratories: Consultancy. Marquez:Johnson & Johnson: Equity Ownership; Janssen: Employment. Desai:Janssen: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Janssen: Employment; Johnson & Johnson: Equity Ownership. Elliott:Millennium: The Takeda Oncology Company: Employment. Shi:Millennium: The Takeda Oncology Company: Employment. Dow:Millennium: The Takeda Oncology Company: Employment. Jobanputra:Millennium: The Takeda Oncology Company: Employment. Esseltine:Millennium: The Takeda Oncology Company: Employment; The Takeda Pharmaceutical Company: Equity Ownership. Niculescu:Millennium: The Takeda Oncology Company: Employment. Anderson:Celgene: Consultancy; Onyx Pharmaceuticals: Consultancy; Sanofi-Aventis: Consultancy; Gilead: Consultancy; Acetylon Pharmaceuticals: Equity Ownership; Oncopep: Equity Ownership. Lonial:Merck: Consultancy; Onyx Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Richardson:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees.
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36

Garcia-Martinez, V., C. Lopez Sanchez, W. Hamed, W. Hamed, JH Hsu, R. Ferrer-Lorente, Maryam Alshamrani, et al. "Poster session 2Morphogenetic mechanisms290MiR-133 regulates retinoic acid pathway during early cardiac chamber specification291Bmp2 regulates atrial differentiation through miR-130 during early heart looping formationDevelopmental genetics294Association of deletion allele of insertion/deletion polymorphism in alpha 2B adrenoceptor gene and hypertension with or without type 2 diabetes mellitus295Association of G1359A polymorphism of the endocannabinoid type 1 receptor (CNR1) with coronary artery disease (CAD) with type 2 diabetes mellitusCell growth, differentiation and stem cells - Vascular298Gamma-secretase inhibitor prevents proliferation and migration of ductus arteriosus smooth muscle cells: a role of Notch signaling in postnatal closure of ductus arteriosus299Mesenchymal stromal-like cells (MLCs) derived from induced pluripotent stem (iPS) cells: a promising therapeutic option to promote neovascularization300Sonic Hedgehog promotes mesenchymal stem cell differentiation to vascular smooth muscle cells in cardiovacsular disease301Proinflammatory cytokine secretion and epigenetic modification in endothelial cells treated LPS-GinfivalisCell death and apoptosis - Vascular304Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipidsTranscriptional control and RNA species - Vascular307MicroRNA-34a role in vascular calcification308Local delivery of a miR-146a inhibitor utilizing a clinically applicable approach attenuates neointima formation after vascular injury309Long noncoding RNA landscape of hypoxic endothelial cells310Specific circulating microRNAs levels associate with hypertension, hyperglycemia and dysfunctional HDL in acute coronary syndrome patientsCytokines and cellular inflammation - Vascular313Phosphodiesterase5A up-regulation in vascular endothelium under pro-inflammatory conditions: a newly disclosed anti-inflammatory activity for the omega-3polyunsaturated aatty acid docosahexaenoic acid314Cardiovascular risk modifying with extra-low dose anticytokine drugs in rhematoid arthritis315Conversion of human M-CSF macrophages into foam cells reduces their proinflammatory responses to classical M1-polarizing activation316Lymphocytic myocarditis coincides with increased plaque inflammation and plaque hemorrhage in coronary arteries, facilitating myocardial infarction317Serum osteoprotegerin level predictsdeclined numerous of circulating endothelial- derived and mononuclear-derived progenitor cells in patients with metabolic syndromeGrowth factors and neurohormones - Vascular320Effect of gastrin-releasing peptide (GRP) on vascular inflammationSignal transduction - Heart323A new synthetic peptide regulates hypertrophy in vitro through means of the inhibition of nfkb324Inducible fibroblast-specific knockout of p38 alpha map kinase is cardioprotective in a mouse model of isoproterenol-induced cardiac hypertrophy325Regulation of beta-adrenoceptor-evoked inotropic responses by inhibitory G protein, adenylyl cyclase isoforms 5 and 6 and phosphodiesterases326Binding to RGS3 and stimulation of M2 muscarinic acetylcholine receptors modulates the substrate specificity of p190RhoGAP in cardiac myocytes327Cardiac regulation of post-translational modifications, parylation and deacetylation in LMNA dilated cardiomyopathy mouse model328Beta-adrenergic regulation of the b56delta/pp2a holoenzyme in cardiac myocytes through b56delta phosphorylation at serine 573Nitric oxide and reactive oxygen species - Vascular331Oxidative stress-induced miR-200c disrupts the regulatory loop among SIRT1, FOXO1 and eNOS332Antioxidant therapy prevents oxidative stress-induced endothelial dysfunction and Enhances Wound Healing333Morphological and biochemical characterization of red blood cell in coronary artery diseaseCytoskeleton and mechanotransduction - Heart336Novel myosin activator, JSH compounds, increased myocardial contractility without chronotropic effect in ratsExtracellular matrix and fibrosis - Vascular339Ablation of Toll-like receptor 9 causes cardiac rupture after myocardial infarction by attenuating proliferation and differentiation of cardiac fibroblasts340Altered vascular remodeling in the mouse hind limb ischemia model in Factor VII activating protease (FSAP) deficiencyVasculogenesis, angiogenesis and arteriogenesis343Pro-angiogenic effects of proly-hydroxylase inhibitors and their potential for use in a novel strategy of therapeutic angiogenesis for coronary total occlusion344Nrf2 drives angiogenesis in transcription-independent manner: new function of the master regulator of oxidative stress response345Angiogenic gene therapy, despite efficient vascular growth, is not able to improve muscle function in normoxic or chronically ischemic rabbit hindlimbs -role of capillary arterialization and shunting346Effect of PAR-1 inhibition on collateral vessel growth in the murine hind limb model347Quaking is a key regulator of endothelial cell differentiation, neovascularization and angiogenesis348"Emerging angiogenesis" in the chick chorioallantoic membrane (CAM). An in vivo study349Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis in vitro and in vivo via EMMPRINEndothelium352Reciprocal regulation of GRK2 and bradykinin receptor stimulation modulate Ca2+ intracellular level in endothelial cells353The roles of bone morphogenetic proteins 9 and 10 in endothelial inflammation and atherosclerosis354The contribution of GPR55 to the L-alpha-lysophosphatidylinositol-induced vasorelaxation in isolated human pulmonary arteries355The endothelial protective ACE inhibitor Zofenoprilat exerts anti-inflammatory activities through H2S production356A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction357Endothelial progenitor cells to apoptotic endothelial cell-derived microparticles ration differentiatesas preserved from reduced ejection fractionheart failure358Proosteogenic genes are activated in endothelial cells of patients with thoracic aortic aneurysm359Endothelin ETB receptors mediate relaxing responses to insulin in pericardial resistance arteries from patients with cardiovascular disease (CVD)Smooth muscle and pericytes362CX3CR1 positive myeloid cells regulate vascular smooth muscle tone by inducing calcium oscillations via activation of IP3 receptors363A novel function of PI3Kg on cAMP regulation, role in arterial wall hyperplasia through modulation of smooth muscle cells proliferation364NRP1 and NRP2 play important roles in the development of neointimal hyperplasia in vivo365Azithromycin induces autophagy in aortic smooth muscle cellsCoagulation, thrombosis and platelets368The real time in vivo evaluation of platelet-dependent aldosterone prothrombotic action in mice369Development of a method for in vivo detection of active thrombi in mice370The antiplatelet effects of structural analogs of the taurine chloramine371The influence of heparin anticoagulant drugs on functional state of human platelets372Regulation of platelet aggregation and adenosine diphosphate release by d dimer in acute coronary syndrome (in vitro study)Oxygen sensing, ischaemia and reperfusion375Sirtuin 5 mediates brain injury in a mouse model of cerebral ischemia-reperfusion376Abscisic acid: a new player in cardiomyocyte protection from ischaemia?377Protective effects of ultramicronized palmitoylethanolamide (PEA-um) in myocardial ischaemia and reperfusion injury in vivo378Identification of stem cell-derived cardiomyocytes using cardiac specific markers and additional testing of these cells in simulated ischemia/reperfusion system379Single-dose intravenous metformin treatment could afford significant protection of the injured rat kidney in an experimental model of ischemia-reperfusion380Cardiotoxicity of long acting muscarinic receptor antagonists used for chronic obstructive pulmonary disease381Dependence antioxidant potential on the concentration of amino acids382The impact of ischemia-reperfusion on physiological parameters,apoptosis and ultrastructure of rabbit myocardium with experimental aterosclerosisMitochondria and energetics385MicroRNA-1 dependent regulation of mitochondrial calcium uniporter (MCU) in normal and hypertrophied hearts386Mitochondrial homeostasis and cardioprotection: common targets for desmin and aB-crystallin387Overexpression of mitofusin-2 (Mfn2) and associated mitochondrial dysfunction in the diabetic heart388NO-dependent prevention of permeability transition pore (MPTP) opening by H2S and its regulation of Ca2+ accumulation in rat heart mitochondria389G protein coupled receptor kinase 2 (GRK2) is fundamental in recovering mitochondrial morphology and function after exposure to ionizing radiation (IR)Gender issues392Sex differences in pulmonary vascular control; focus on the nitric oxide pathwayAging395Heart failure with preserved ejection fraction develops when feeding western diet to senescence-accelerated mice396Cardiovascular markers as predictors of cognitive decline in elderly hypertensive patients397Changes in connexin43 in old rats with volume overload chronic heart failureGenetics and epigenetics400Calcium content in the aortic valve is associated with 1G>2G matrix metalloproteinase 1 polymorphism401Neuropeptide receptor gene s (NPSR1) polymorphism and sleep disturbances402Endothelin-1 gene Lys198Asn polymorphism in men with essential hypertension complicated and uncomplicated with chronic heart failure403Association of common polymorphisms of the lipoprotein lipase and pon1 genes with the metabolic syndrome in a sample of community participantsGenomics, proteomics, metabolomics, lipidomics and glycomics405Gene expression quantification using multiplexed color-coded probe pairs to determine RNA content in sporadic cardiac myxoma406Large-scale phosphorylation study of the type 2 diabetic heart subjected to ischemia / reperfusion injury407Transcriptome-based identification of new anti-inflammatory properties of the olive oil hydroxytyrosol in vascular endothelial cell under basal and proinflammatory conditions408Gene polymorphisms combinations and risk of myocardial infarctionComputer modelling, bioinformatics and big data411Comparison of the repolarization reserve in three state-of-the-art models of the human ventricular action potentialMetabolism, diabetes mellitus and obesity414Endothelial monocyte-activating polypeptide-II improves heart function in type -I Diabetes mellitus415Admission glucose level is independent predictor of impaired left ventricular function in patients with acute myocardial infarction: a two dimensional speckle-tracking echocardiography study416Association between biochemical markers of lipid profile and inflammatory reaction and stiffness of the vascular wall in hypertensive patients with abdominal obesity417Multiple common co-morbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress and myocardial stiffening418Investigating the cardiovascular effects of antiretroviral drugs in a lean and high fat/sucrose diet rat model of obesity419Statins in the treatment of non-alcoholic steatohepatitis (NASH). Our experience from a 2-year prospective study in Constanta County, Romania420Epicardial adipose tissue as a predictor of cardiovascular outcome in patients with ACS undergoing PCI?Arterial and pulmonary hypertension423Dependence between heart rhythm disorers and ID polymorphism of ACE gene in hypertensive patients424Molecular mechanisms underlying the beneficial effects of Urocortin 2 in pulmonary arterial hypertension425Inhibition of TGf-b axis and action of renin-angiotensin system in human ascending aorta aneurysms426Early signs of microcirculation and macrocirculation abnormalities in prehypertension427Vascular smooth muscle cell-expressed Tie-2 controls vascular tone428Cardiac and vascular remodelling in the development of chronic thrombo-embolic pulmonary hypertension in a novel swine modelBiomarkers431Arrhythmogenic cardiomyopathy: a new, non invasive biomarker432Can circulating microRNAs distinguish type 1 and type 2 myocardial infarction?433Design of a high-throughput multiplex proteomics assay to identify left ventricular diastolic dysfunction in diabetes434Monocyte-derived and P-selectin-carrying microparticles are differently modified by a low fat diet in patients with cardiovascular risk factors who will and who will not develop a cardiovascular event435Red blood cell distribution width assessment by polychromatic interference microscopy of thin films in chronic heart failure436Invasive and noninvasive evaluation of quality of radiofrequency-induced cardiac denervation in patients with atrial fibrillation437The effect of therapeutic hypothermia on the level of brain derived neurotrophic factor (BDNF) in sera following cardiopulmonary resustitation438Novel biomarkers to predict outcome in patients with heart failure and severe aortic stenosis439Biological factors linking depression and anxiety to cardiovascular disease440Troponins and myoglobin dynamic at coronary arteries graftingInvasive, non-invasive and molecular imaging443Diet composition effects on the genetic typing of the mouse ob mutation: a micro-ultrasound characterization of cardiac function, macro and micro circulation and liver steatosis444Characterization of pig coronary and rabbit aortic lesions using IV-OCT quantitative analysis: correlations with histologyGene therapy and cell therapy447Enhancing the survival and angiogenic potential of mouse atrial mesenchymal cells448VCAM-1 expression in experimental myocardial infarction and its relation to bone marrow-derived mononuclear cell retentionTissue engineering451Advanced multi layered scaffold that increases the maturity of stem cell-derived human cardiomyocytes452Response of engineered heart tissue to simulated ischemia/reperfusion in the presence of acute hyperglycemic conditions453Serum albumin hydrogels prevent de-differentiation of neonatal cardiomyocytes454A novel paintbrush technique for transfer of low viscosity ultraviolet light curable cyan methacrylate on saline immersed in-vitro sheep heart." Cardiovascular Research 111, suppl 1 (July 1, 2016): S56—S81. http://dx.doi.org/10.1093/cvr/cvw149.

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37

Liang, Yong, Xiaohu Chen, Zhenglong Sun, Gang Wen, Chong Chen, Libo Wang, Xin Jin, et al. "High Dynamic Range Structured Illumination Microscope Based on Multiple Exposures." Frontiers in Physics 9 (March 10, 2021). http://dx.doi.org/10.3389/fphy.2021.648174.

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Structured illumination microscope (SIM) can double the spatial resolution by using fringed pattern illumination. However, for samples with large intra-scene dynamic ranges, such as clustered objects, SIM fails to reconstruct high-quality images and often exhibits strong artifacts. Herein, we present a high dynamic range SIM (HDR-SIM) method using a multi-exposure acquisition strategy. With HDR-SIM, individual and clustered microspheres and vesicles with 420 times intensity differences can be visualized in the same scene while the delicate structures of the sample were preserved effectively.
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Karr, Brian A., Kurt Debattista, and Alan G. Chalmers. "Optical effects on HDR calibration via a multiple exposure noise-based workflow." Visual Computer, April 18, 2020. http://dx.doi.org/10.1007/s00371-020-01841-5.

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Gailloud, Leslie, Tatiana Gonzalez-Argoti, Sophia Philip, Lena S. Josephs, Joanne E. Mantell, and Laurie J. Bauman. "‘How come they don’t talk about it in school?’ Identifying adolescent barriers to PrEP use." Health Education Research, September 1, 2021. http://dx.doi.org/10.1093/her/cyab030.

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Abstract Although 21% of new human immunodeficiency virus (HIV) diagnoses in the United States are in youth aged 13–24 years, adolescent awareness and uptake of the HIV prevention medication pre-exposure prophylaxis (PrEP) are low. This study explores the attitudes and challenges that adolescents face while taking PrEP. Thirty interviews were conducted with Black and Latine (we use the gender-inclusive term Latine rather than Latinx for more appropriate Spanish pronunciation) students aged 15–17 who received care at school-based health centers (SBHCs) in the Bronx, NY. Transcripts were coded inductively and deductively using thematic analysis. Most participants were unaware of PrEP, but nearly all were enthusiastic when informed about it; a majority denied that they would feel any stigma when taking PrEP. Despite this high receptivity, multiple barriers were identified, particularly confidentiality from parents, low perceived need of PrEP and concerns about daily adherence and side effects. Adolescents overall were enthusiastic about the availability of PrEP and felt it empowered them to have control over their health. SBHCs were considered trusted sources of confidential, accessible care, and we believe that they can be uniquely positioned to mitigate barriers to PrEP distribution in the future.
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40

Herrington, Josiah, Clara Ferreira, Yong Chen, and Salahuddin Ahmad. "Neutron radiation effects on microcomputers in radiation therapy environments." Journal of Radiotherapy in Practice, September 8, 2020, 1–4. http://dx.doi.org/10.1017/s1460396920000734.

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Abstract Aim: Microcomputers play an increasingly important role in the delivery of radiation therapy. Exposure to neutron irradiation can produce undesirable effects in modern microcomputers. The objective of this study is to measure acute and cumulative effects of neutron exposure of Intel-based microcomputers in photon and proton therapy treatment environments. Materials and methods: Multiple computers were irradiated with neutrons produced from MEVION S250 passive scattering proton therapy and from Varian 21EX Linear Accelerator photon therapy systems. The energy of the proton beam was 232 MeV and the photon beam energies were 6 and 18 MV. Rates of fatal errors in computer processing unit (CPU) cores were measured. Results: Varying rates of fatal system errors due to upsets in the CPU cores were observed. Post-exposure routine stress testing revealed no permanent hardware defects in the random access memory (RAM) or hard disk drive (HDD) of any tested systems. Microchip manufacturers fit increasingly high numbers of transistors in the same volume and the susceptibility to radiation thus increases. Conclusions: This work explores if the process size of a microchip is the dominant factor and also looked at the short- and long-term effects of neutron irradiation on modern microprocessors in a clinical environment. Additionally, methods of effective shielding are proposed.
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41

Izmir Güner, Șebnem, Mustafa Teoman Yanmaz, Ahmet Selvi, and Cigdem Usul. "The high effect of chemomobilization with high-dose etopside + granulocyte-colony stimulating factor in autologous hematopoietic peripheral blood stem cell transplantation: a single center experience." Hematology Reports 8, no. 1 (March 18, 2016). http://dx.doi.org/10.4081/hr.2016.6319.

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Autologous hematopoietic stem cell transplantation (auto-HSCT) provides hematopoietic support after high-dose chemotherapy and is the standard of care for patients with multiple myeloma (MM), chemo sensitive relapsed high or intermediate grade non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL). However, yields of hematopoietic stem cells vary greatly between patients, and the optimal strategy to mobilize hematopoietic stem cells into peripheral blood for collection has not been defined yet. We investigated the efficacy and safety of chemo mobilization with an intermediate dose etoposide (VP-16; 200 mg/m2 on days 1-3) and granulocyte-colony stimulating factor (G-CSF)(5 μg/kg twice daily from day 4 through the final day of collection). We reviewed our institutional experience with 91 patients (71 MM, 12 HL, 8 NHL) mobilized with this regimen. VP-16 + G-CSF resulted in successful mobilization in 95.55% of the patients (on one patient stem cell collection with plerixafor was applied), including 76 patients (83.52%) whose stem cells were collected successfully in a single day. Collection was managed between min. D8 and max. D17. Patient age, gender, exposure to previous irradiation and chemotherapy, previous mobilization attempts, and disease characteristics were not considered during selection. Adverse effects of the regimen included supportive transfusions and fevers requiring hospitalization or intravenous antibiotics. VP-16 and GCSF appears to be a safe and effective mobilization regimen for patients with multiple myeloma, non-Hodgkin’s lymphoma and Hodgkin’s lymphoma undergoing autologous stem cell transplantation, producing excellent stem cell yield with the majority of patients requiring 1 day of apheresis.
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Nghi, Do Huu, Vo Thi Ngoc Hao, and Nguyen Thi Hong Nhung. "Experimental Application of High-content Screening in Evaluating the Induction of Cell-cycle Arrest and Apoptosis on Human Liver Cancer Cell Line Hep-G2." VNU Journal of Science: Medical and Pharmaceutical Sciences 36, no. 4 (December 19, 2020). http://dx.doi.org/10.25073/2588-1132/vnumps.4248.

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This study discusses the results of the experimental application of high-content screening (HCS) techniques in evaluating the induction of cell-cycle arrest and apoptosis on human liver cancer cell line, Hep-G2. Accordingly, the bisbenzimide-stained cells (Hoechst 33342; 350 to 500 nM) were analyzed by using an Olympus scanˆR HCS-system to determine the cell-cycle phases (G1, S, and G2/M) and apoptosis as well. As a result, the cell-cycle arrest could be indicated by an increase in G2/M population of Hep-G2 cells after 24h exposure to zerumbone (Zer4; 9 µg/mL) and a similar observation could be made for paclitaxel (Pac; 4 µg/mL) as a reference substance. Keywords Apoptosis, cell-cycle arrest, high-content screening, human liver cancer cell line Hep-G2. References [1] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (2011) 646–674.[2] M. Malumbres, M. Barbacid, Cell cycle, CDKs and cancer: a changing paradigm, Nat. Rev. Cancer 9 (2009) 153–166.[3] S. Diermeier-Daucher, et al., Cell type specific applicability of 5-ethynyl-2'-deoxyuridine (EdU) for dynamic proliferation assessment in flow cytometry, Cytometry A 75 (2009) 535-546.[4] J. Essers, et al., Nuclear dynamics of PCNA in DNA replication and repair, Mol. Cell Biol 25 (2005) 9350- 9359. [5] V. Roukos, et al., Dynamic recruitment of licensing factor Cdt1 to sites of DNA damage. J. Cell Sci. 124 (2011) 422-434.[6] M. Hesse, et al., Direct visualization of cell division using high-resolution imaging of M-phase of the cell cycle, Nat. Commun 3 (2012) 1076. doi: 10.1038/ncomms2089.[7] P. Cappella, F. Gasparri, M. Pulici, J. Moll, A novel method based on click chemistry, which overcomes limitations of cell cycle analysis by classical determination of BrdU incorporation, allowing multiplex antibody staining, Cytometry A 73 (2008) 626–636. [8] S. Diermeier-Daucher, et al., Cell type specific applicability of 5-ethynyl-2’-deoxyundine (EdU) for dynamic proliferation assessment in flow cytometry, Cytometry A 75 (2009) 535–546.[9] T. Yokochi, D.M. Gilbert, Replication labeling with halogenated thymidine analogs, Curr. Protoc. Cell Biol, 35 (2007) 22.10.1–22.10.14. [10] T.J. McGarry, M.W. Kirschner, Geminin, an inhibitor of DNA replication, is degraded during mitosis, Cell 93 (1998) 1043–1053. [11] H. Nishitani, S. Taraviras, Z. Lygerou, T. Nishimoto, The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S-phase. J. Biol. Chem 276 (2001) 44905–44911.[12] J. Pines, T. Hunter, Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B, Nature 346 (1990) 760–763. [13] A. Stathopoulou, et al., Cdt1 is differentially targeted for degradation by anticancer chemotherapeutic drugs. PLoS ONE 7, e34621 (2012). [14] M. Hesse, A. Raulf, G.A. Pilz, C. Haberlandt, A.M. Klein, R. Jabs, H. Zaehres, C.J. Fügemann, K. Zimmermann, J. Trebicka, A. Welz, A. Pfeifer, W. Röll, M.I. Kotlikoff, C. Steinhäuser, M. Götz, H.R. Schöler, B.K. Fleischmann, Direct visualization of cell division using high-resolution imaging of M-phase of the cell cycle, Nat. Commun 3 (2012): 1076.[15] D.A. Ridenour, M.C. McKinney, C.M. Bailey, P.M. Kulesa, CycleTrak: a novel system for the semiautomated analysis of cell cycle dynamics. Dev. Biol 365 (2012) 189–195. [16] A. Roukos, et al., Cell cycle staging of individual cells by fluorescence microscopy, Nat. Protoc 10 (2015) 334-348.[17] E. Harlow, D. Lane, Fixing attached cells in paraformaldehyde, CSH Protoc 3 (2006) doi: 10.1101/pdb.prot4294.[18] G. Mazzini, M. Danova, Fluorochromes for DNA staining and quantitation, Method. Mol. Biol 1560 (2017) 239-259.[19] A. Gottfried, E. Weinhold, Sequence-specific covalent labelling of DNA, Biochem. Soc. Trans 39 (2011) 623-628.[20] J. Bucevičius, G. Lukinavičius, R. Gerasimaitė, The use of Hoechst dyes for DNA staining and beyond, Chemosensor 6 (2018) 1-18.[21] V. Kumar, A.K. Abbas, J.C. Aster, Robbins and Cotran Pathologic Basis of Disease, Ninth ed., Elsevier/Saunders, Philadelphia (2015).[22] N.A. Jensen et al., Establishment of a high content assay for the identification and characterisation of bioactivities in crude bacterial extracts that interfere with the eukaryotic cell cycle, J. Biotechnol 140 (2009) 124-134.[23] H.S. Rahman, et al., Zerumbone induces G2/M cell cycle arrest and apoptosis via mitochondrial pathway in Jurkat cell line, Nat. Prod. Commun 9 (2014) 1237-1242.[24] S.I. Abdelwahab, et al., Zerumbone inhibits interleukin-6 and induces apoptosis and cell cycle arrest in ovarian and cervical cancer cells, Intern. Immunopharm 12 (2012) 594-602.[25] M. Xian, et al., Zerumbone, A bioactive sesquiterpene, induces G2/M cell cycle arrest and apoptosis in leukemia cells via a Fas- and mitochondria-mediated pathway, Cancer Sci 98 (2007) 118-126.[26] A. Sehrawat, et al., Zerumbone causes Bax-and Bak-mediated apoptosis in human breast cancer cells and inhibits orthotopic xenograft growth in vivo, Breast Cancer Res. Treat. 136 (2012) 429-441.[27] Y.Z. Zhou, et al., Zerumbone induces G1 cell cycle arrest and apoptosis in cervical carcinoma cells, Int. J. Clin. Exp. Med. 10 (2017) 6640-6647.
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Nafstad, Per, Sven O. Samuelsen, Lorentz M. Irgens, and Tor Bjerkedal. "Svangerskapskomplikasjoner og risikoen for astma blant nordmenn født 1967-1993." Norsk Epidemiologi 15, no. 1 (October 13, 2009). http://dx.doi.org/10.5324/nje.v15i1.226.

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<strong><em><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left">Bakgrunn</p></font></font></em></strong></span><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left"> </p></font></em></strong></span><p align="left"> </p><strong><em><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left">Metode</p></font></font></em></strong></span><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left"> </p></font></em></strong></span><p align="left"> </p><strong><em><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left">Resultater</p></font></font></em></strong></span><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left"> </p></font></em></strong></span><p align="left"> </p><strong><em><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left">Konklusjon</p></font></font></em></strong></span><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left"> </p></font></em></strong></span><p align="left"> </p><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><strong><em><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left">Background</p></font></font></em></strong></span><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left"> </p></font></em></strong></span><p align="left"> </p><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;">: Fetal life events may affect the development of the immune and/or respiratory system and increase the risk of asthma and allergic diseases. The objective of this study was to test the hypothesis that pregnancy complications are associated with the risk of developing asthma in the offspring.</span></span><strong><em><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left">Methods</p></font></font></em></strong></span><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left"> </p></font></em></strong></span><p align="left"> </p><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;">: The study population comprised Norwegian live births 1967-1993 (n = 1 548 429) linking the Medical Birth Registry of Norway (MBRN) (exposure variables) and the National Insurance Administration Register (NIAR) (outcome variables), which covers all Norwegians. The MBRN variables included pregnancy complications, pregnancy outcomes and diseases of the mother. The NIAR provided data on all Norwegians who had received cash benefit for treatment of asthma from 1967 to 1996 (n = 5938, 3.9/1000 persons).</span></span><strong><em><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left">Results</p></font></font></em></strong></span><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left"> </p></font></em></strong></span><p align="left"> </p><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;">: In multiple logistic regression analysis, pregnancy complications (International Classification of Diseases (ICD)-8 codes: 630-34) were associated with the risk of asthma (odds ratio 1.82, 95% confidence interval: 1.67–1.98). This was also the case if analyses were performed in different strata according to year of birth, plurality, maternal atopy, geographical district of birth, and maternal education.</span></span><strong><em><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><span style="font-size: x-small; font-family: TimesNewRomanPS-BoldItalicMT;"><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left">Conclusions</p></font></font></em></strong></span><strong><em><font face="TimesNewRomanPS-BoldItalicMT" size="2"><p align="left"> </p></font></em></strong></span><p align="left"> </p><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;">: Pregnancy complications may represent risk factors for the development of asthma in the offspring or express early signs of increased risk for developing the disease.</span></span></em></strong></em></strong></em></strong></em></strong></span></span></em><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;">: Svangerskapskomplikasjoner hos mor kan gi økt risiko for utvikling av astma hos barnet eller utrykke tidlige tegn på økt risiko for å utvikle sykdommen</span></span></strong></em><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;">: Multipell logistisk regresjonsanalyse viste at svangerskapskomplikasjoner (International Classification of Diseases (ICD)-8 kode 630-34) var assosiert med risikoen for å ha fått grunn- og/eller hjelpestønad for astma (odds ratio 1,82, 95% konfidensintervall: 1,67–1,98). Dette var også tilfelle hvis analysene ble utført i forskjellige strata av fødselsår, pluralitet, atopisk sykdom hos mor, utdanningsnivå hos mor og hvor i landet fødselen fant sted.</span></span></strong></em><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;">: Undersøkelsespopulasjonen består av levende fødte nordmenn født i perioden 1967-1993(n = 1 548 429). Opplysninger fra Medisinsk fødselsregister (MFR) ble koblet med opplysninger fra Rikstrygdeverket om mottatt grunn- og hjelpestønad. Fødselsregisteret inneholder opplysninger om svangerskapskomplikasjoner og sykdommer hos den gravide/fødende mor og Rikstrygdeverkets register inneholder opplysninger og diagnoser over alle nordmenn som har motatt grunn- og hjelpestønad pga. astma i perioden 1967-1996 (n = 5938, 3,9/1000 personer).</span></span></strong></em><span style="font-size: x-small; font-family: TimesNewRomanPSMT;"><span style="font-size: x-small; font-family: TimesNewRomanPSMT;">: Det er mulig at forhold og hendelser i svangerskapet kan påvirke utviklingen av immunog/eller respirasjonssystemet og dermed øke risikoen for å utvikle astma og allergiske lidelser. I denne artikkelen testes hypotesen om hvorvidt svangerskapskomplikasjoner påvirker risikoen for at barn utvikler astma.</span></span></strong>
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