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2. |
- Menden, MP, et al.
(author)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Journal article (peer-reviewed)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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3. |
- Margutti, R., et al.
(author)
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A PANCHROMATIC VIEW OF THE RESTLESS SN 2009ip REVEALS THE EXPLOSIVE EJECTION OF A MASSIVE STAR ENVELOPE
- 2014
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 780:1
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Journal article (peer-reviewed)abstract
- The double explosion of SN 2009ip in 2012 raises questions about our understanding of the late stages of massive star evolution. Here we present a comprehensive study of SN 2009ip during its remarkable rebrightenings. High-cadence photometric and spectroscopic observations from the GeV to the radio band obtained from a variety of ground-based and space facilities (including the Very Large Array, Swift, Fermi, Hubble Space Telescope, and XMM) constrain SN 2009ip to be a low energy (E similar to 1050 erg for an ejecta mass similar to 0.5 M-circle dot) and asymmetric explosion in a complex medium shaped by multiple eruptions of the restless progenitor star. Most of the energy is radiated as a result of the shock breaking out through a dense shell of material located at similar to 5 x 10(14) cm with M similar to 0.1 M-circle dot, ejected by the precursor outburst similar to 40 days before the major explosion. We interpret the NIR excess of emission as signature of material located further out, the origin of which has to be connected with documented mass-loss episodes in the previous years. Our modeling predicts bright neutrino emission associated with the shock break-out if the cosmic-ray energy is comparable to the radiated energy. We connect this phenomenology with the explosive ejection of the outer layers of the massive progenitor star, which later interacted with material deposited in the surroundings by previous eruptions. Future observations will reveal if the massive luminous progenitor star survived. Irrespective of whether the explosion was terminal, SN 2009ip brought to light the existence of new channels for sustained episodic mass loss, the physical origin of which has yet to be identified.
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4. |
- Orsini, S., et al.
(author)
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Inner southern magnetosphere observation of Mercury via SERENA ion sensors in BepiColombo mission
- 2022
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Mercury’s southern inner magnetosphere is an unexplored region as it was not observed by earlier space missions. In October 2021, BepiColombo mission has passed through this region during its first Mercury flyby. Here, we describe the observations of SERENA ion sensors nearby and inside Mercury’s magnetosphere. An intermittent high-energy signal, possibly due to an interplanetary magnetic flux rope, has been observed downstream Mercury, together with low energy solar wind. Low energy ions, possibly due to satellite outgassing, were detected outside the magnetosphere. The dayside magnetopause and bow-shock crossing were much closer to the planet than expected, signature of a highly eroded magnetosphere. Different ion populations have been observed inside the magnetosphere, like low latitude boundary layer at magnetopause inbound and partial ring current at dawn close to the planet. These observations are important for understanding the weak magnetosphere behavior so close to the Sun, revealing details never reached before.
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5. |
- Kangas, T., et al.
(author)
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Supernova 2013fc in a circumnuclear ring of a luminous infrared galaxy : the big brother of SN 1998S
- 2016
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 456:1, s. 323-346
-
Journal article (peer-reviewed)abstract
- We present photometric and spectroscopic observations of SN 2013fc, a bright type II supernova (SN) in a circumnuclear star-forming ring in the luminous infrared galaxy ESO 154-G010, observed as part of the Public ESO Spectroscopic Survey of Transient Objects. SN 2013fc is both photometrically and spectroscopically similar to the well-studied type IIn SN 1998S and to the bright type II-L SN 1979C. It exhibits an initial linear decline, followed by a short plateau phase and a tail phase with a decline too fast for Co-56 decay with full. gamma-ray trapping. Initially, the spectrum was blue and featureless. Later on, a strong broad (similar to 8000 km s(-1)) H alpha emission profile became prominent. We apply a STARLIGHT stellar population model fit to the SN location (observed when the SN had faded) to estimate a high extinction of A(V) = 2.9 +/- 0.2 mag and an age of 10(+ 3) (- 2) Myr for the underlying cluster. We compare the SN to SNe 1998S and 1979C and discuss its possible progenitor star considering the similarities to these events. With a peak brightness of B = - 20.46 +/- 0.21 mag, SN 2013fc is 0.9 mag brighter than SN 1998S and of comparable brightness to SN 1979C. We suggest that SN 2013fc was consistent with a massive red supergiant (RSG) progenitor. Recent mass loss probably due to a strong RSG wind created the circumstellar matter illuminated through its interaction with the SN ejecta. We also observe a near- infrared excess, possibly due to newly condensed dust.
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11. |
- Farzan, N, et al.
(author)
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Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium
- 2017
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In: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 18:10, s. 931-943
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Journal article (peer-reviewed)abstract
- Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. Materials & methods: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. Results: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. Conclusion: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.
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12. |
- Fox, Ori D., et al.
(author)
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The slow demise of the long-lived SN 2005ip
- 2020
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 498:1, s. 517-531
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Journal article (peer-reviewed)abstract
- The Type IIn supernova (SN IIn) 2005ip is one of the most well-studied and long-lasting examples of an SN interacting with its circumstellar environment. The optical light curve plateaued at a nearly constant level for more than five years, suggesting ongoing shock interaction with an extended and clumpy circumstellar medium (CSM). Here, we present continued observations of the SN from ∼1000 to 5000 d post-explosion at all wavelengths, including X-ray, ultraviolet, near-infrared (NIR), and mid-infrared. The UV spectra probe the pre-explosion mass loss and show evidence for CNO processing. From the bolometric light curve, we find that the total radiated energy is in excess of 1050 erg, the progenitor star’s pre-explosion mass-loss rate was ≳1×10−2M⊙ yr−1, and the total mass lost shortly before explosion was ≳1M⊙, though the mass lost could have been considerably larger depending on the efficiency for the conversion of kinetic energy to radiation. The ultraviolet through NIR spectrum is characterized by two high-density components, one with narrow high-ionization lines, and one with broader low-ionization H i, He i, [O i], Mg ii, and Fe ii lines. The rich Fe ii spectrum is strongly affected by Lyα fluorescence, consistent with spectral modelling. Both the Balmer and He i lines indicate a decreasing CSM density during the late interaction period. We find similarities to SN 1988Z, which shows a comparable change in spectrum at around the same time during its very slow decline. These results suggest that, at long last, the shock interaction in SN 2005ip may finally be on the decline.
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13. |
- Szalai, Tamás, et al.
(author)
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Spitzer's Last Look at Extragalactic Explosions : Long-term Evolution of Interacting Supernovae
- 2021
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 919:1
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Journal article (peer-reviewed)abstract
- Here we present new, yet final, mid-infrared (mid-IR) data for supernovae (SNe) based on measurements with the Spitzer Space Telescope. Comparing our recent 3.6 and 4.5 mu m photometry with previously published mid-IR and further multiwavelength data sets, we were able to draw some conclusions about the origin and heating mechanism of the dust in these SNe or in their environments, as well as about possible connection with circumstellar matter (CSM) originating from pre-explosion mass-loss events in the progenitor stars. We also present new results regarding both certain SN classes and single objects. We highlight the mid-IR homogeneity of SNe Ia-CSM, which may be a hint of their common progenitor type and of their basically uniform circumstellar environments. Regarding single objects, it is worth highlighting the late-time interacting Type Ib SNe 2003gk and 2004dk, for which we present the first-ever mid-IR data, which seem to be consistent with clues of ongoing CSM interaction detected in other wavelength ranges. Our current study suggests that long-term mid-IR follow-up observations play a key role in a better understanding of both pre- and post-explosion processes in SNe and their environments. While Spitzer is not available anymore, the expected unique data from the James Webb Space Telescope, as well as long-term near-IR follow-up observations of dusty SNe, can bring us closer to the hidden details of this topic.
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14. |
- Wollenberg, A., et al.
(author)
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ETFAD/EADV Eczema task force 2020 position paper on diagnosis and treatment of atopic dermatitis in adults and children
- 2020
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In: Journal of the European Academy of Dermatology and Venereology. - : Wiley. - 0926-9959 .- 1468-3083. ; 34:12, s. 2717-2744
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Journal article (peer-reviewed)abstract
- Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease. The diagnosis is made using evaluated clinical criteria. Disease activity and burden are best measured with a composite score, assessing both objective and subjective symptoms, such as SCORing Atopic Dermatitis (SCORAD). AD management must take into account clinical and pathogenic variabilities, the patient’s age and also target flare prevention. Basic therapy includes hydrating and barrier-stabilizing topical treatment universally applied, as well as avoiding specific and unspecific provocation factors. Visible skin lesions are treated with anti-inflammatory topical agents such as corticosteroids and calcineurin inhibitors (tacrolimus and pimecrolimus), which are preferred in sensitive locations. Topical tacrolimus and some mid-potency corticosteroids are proven agents for proactive therapy, which is defined as the long-term intermittent anti-inflammatory therapy of frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is a rapidly changing field requiring monitoring. Oral corticosteroids have a largely unfavourable benefit–risk ratio. The IL-4R-blocker dupilumab is a safe, effective and licensed, but expensive, treatment option with potential ocular side-effects. Other biologicals targeting key pathways in the atopic immune response, as well as different Janus kinase inhibitors, are among emerging treatment options. Dysbalanced microbial colonization and infection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) only have limited effects on AD-related itch and eczema lesions. Adjuvant therapy includes UV irradiation, preferably narrowband UVB or UVA1. Coal tar may be useful for atopic hand and foot eczema. Dietary recommendations should be patient-specific, and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. Efficacy-proven 'Eczema school' educational programmes and therapeutic patient education are recommended for both children and adults.
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15. |
- Barna, Barnabas, et al.
(author)
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SN 2019muj-a well-observed Type Iax supernova that bridges the luminosity gap of the class
- 2021
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 501:1, s. 1078-1099
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Journal article (peer-reviewed)abstract
- We present early-time (t < +50 d) observations of SN 2019muj (=ASASSN-19tr), one of the best-observed members of the peculiar SN Iax class. Ultraviolet and optical photometric and optical and near-infrared spectroscopic follow-up started from similar to 5 d before maximum light [t(max)(B) on 58707.8 MJD] and covers the photospheric phase. The early observations allow us to estimate the physical properties of the ejecta and characterize the possible divergence from a uniform chemical abundance structure. The estimated bolometric light-curve peaks at 1.05 x 10(42) erg s(-1) and indicates that only 0.031 M-circle dot of Ni-56 was produced, making SN 2019muj a moderate luminosity object in the Iax class with peak absolute magnitude of M-V = -16.4 mag. The estimated date of explosion is t(0) = 58698.2 MJD and implies a short rise time of t(rise) = 9.6 d in B band. We fit of the spectroscopic data by synthetic spectra, calculated via the radiative transfer code TARDIS. Adopting the partially stratified abundance template based on brighter SNe Iax provides a good match with SN 2019muj. However, without earlier spectra, the need for stratification cannot be stated in most of the elements, except carbon, which is allowed to appear in the outer layers only. SN 2019muj provides a unique opportunity to link extremely low-luminosity SNe Iax to well-studied, brighter SNe Iax.
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16. |
- Bergmeister, Konstantin D., et al.
(author)
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Broadband prosthetic interfaces: Combining nerve transfers and implantable multichannel EMG technology to decode spinal motor neuron activity
- 2017
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In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 11, s. 1-8
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Journal article (peer-reviewed)abstract
- Modern robotic hands/upper limbs may replace multiple degrees of freedom of extremity function. However, their intuitive use requires a high number of control signals, which current man-machine interfaces do not provide. Here, we discuss a broadband control interface that combines targeted muscle reinnervation, implantable multichannel electromyographic sensors, and advanced decoding to address the increasing capabilities of modern robotic limbs. With targeted muscle reinnervation, nerves that have lost their targets due to an amputation are surgically transferred to residual stump muscles to increase the number of intuitive prosthetic control signals. This surgery re-establishes a nerve-muscle connection that is used for sensing nerve activity with myoelectric interfaces. Moreover, the nerve transfer determines neurophysiological effects, such as muscular hyper-reinnervation and cortical reafferentation that can be exploited by the myoelectric interface. Modern implantable multichannel EMG sensors provide signals from which it is possible to disentangle the behavior of single motor neurons. Recent studies have shown that the neural drive to muscles can be decoded from these signals and thereby the user's intention can be reliably estimated. By combining these concepts in chronic implants and embedded electronics, we believe that it is in principle possible to establish a broadband man-machine interface, with specific applications in prosthesis control. This perspective illustrates this concept, based on combining advanced surgical techniques with recording hardware and processing algorithms. Here we describe the scientific evidence for this concept, current state of investigations, challenges, and alternative approaches to improve current prosthetic interfaces.
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17. |
- Bergmeister, Konstantin D, et al.
(author)
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Peripheral nerve transfers change target muscle structure and function
- 2019
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In: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:1
-
Journal article (peer-reviewed)abstract
- Selective nerve transfers surgically rewire motor neurons and are used in extremity reconstruction to restore muscle function or to facilitate intuitive prosthetic control. We investigated the neurophysiological effects of rewiring motor axons originating from spinal motor neuron pools into target muscles with lower innervation ratio in a rat model. Following reinnervation, the target muscle's force regenerated almost completely, with the motor unit population increasing to 116% in functional and 172% in histological assessments with subsequently smaller muscle units. Muscle fiber type populations transformed into the donor nerve's original muscles. We thus demonstrate that axons of alternative spinal origin can hyper-reinnervate target muscles without loss of muscle force regeneration, but with a donor-specific shift in muscle fiber type. These results explain the excellent clinical outcomes following nerve transfers in neuromuscular reconstruction. They indicate that reinnervated muscles can provide an accurate bioscreen to display neural information of lost body parts for high-fidelity prosthetic control.
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18. |
- Haak-Frendscho, M, et al.
(author)
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Histidine decarboxylase expression in human melanoma.
- 2000
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In: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 115:3, s. 345-52
-
Journal article (peer-reviewed)abstract
- Histamine has been implicated as one of the mediators involved in regulation of proliferation in both normal and neoplastic tissues. Histidine decarboxylase, the only enzyme that catalyzes the formation of histamine from L-histidine, is an essential regulator of histamine levels. In this study, we investigated the gene and protein expression of histidine decarboxylase in melanoma. Reverse transcriptase polymerase chain reaction and in situ hybridization studies of WM-35, WM-983/B, HT-168, and M1 human melanoma cell lines both resulted in positive signals for histidine decarboxylase messenger RNA. A polyclonal chicken antibody was developed against human histidine decarboxylase and protein expression was confirmed by western blot analysis of the cell lysates, revealing a predominant immunoreactive band at approximately 54 kDa corresponding to monomeric histidine decarboxylase. Protein expression of histidine decarboxylase was also shown by flow cytometric analysis and strong punctate cytoplasmic staining of melanoma cell lines. Moreover, both primary and metastatic human melanoma tissues were brightly stained for histidine decarboxylase. When compared with the very weak or no reactions on cultivated human melanocytes both western blot and immunohistochemical studies showed much stronger histidine decarboxylase expression in melanoma cells. These findings suggest that expression of histidine decarboxylase is elevated in human melanoma.
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19. |
- Sagi, JC, et al.
(author)
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Pharmacogenetics of the Central Nervous System-Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia
- 2021
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In: Cancers. - : MDPI AG. - 2072-6694. ; 13:10
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Journal article (peer-reviewed)abstract
- Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.
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20. |
- Shahbandeh, Melissa, et al.
(author)
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JWST observations of dust reservoirs in type IIP supernovae 2004et and 2017eaw
- 2023
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In: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 523:4, s. 6048-6060
-
Journal article (peer-reviewed)abstract
- Supernova (SN) explosions have been sought for decades as a possible source of dust in the Universe, providing the seeds of galaxies, stars, and planetary systems. SN 1987A offers one of the most promising examples of significant SN dust formation, but until the James Webb Space Telescope (JWST), instruments have traditionally lacked the sensitivity at both late times (>1 yr post-explosion) and longer wavelengths (i.e. >10 μm) to detect analogous dust reservoirs. Here we present JWST/MIRI observations of two historic Type IIP SNe, 2004et and SN 2017eaw, at nearly 18 and 5 yr post-explosion, respectively. We fit the spectral energy distributions as functions of dust mass and temperature, from which we are able to constrain the dust geometry, origin, and heating mechanism. We place a 90 per cent confidence lower limit on the dust masses for SNe 2004et and 2017eaw of >0.014 and >4 × 10−4 M⊙, respectively. More dust may exist at even colder temperatures or may be obscured by high optical depths. We conclude dust formation in the ejecta to be the most plausible and consistent scenario. The observed dust is radiatively heated to ∼100–150 K by ongoing shock interaction with the circumstellar medium. Regardless of the best fit or heating mechanism adopted, the inferred dust mass for SN 2004et is the second highest (next to SN 1987A) mid-infrared inferred dust mass in extragalactic SNe thus far, promoting the prospect of SNe as potential significant sources of dust in the Universe.
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21. |
- Wollenberg, A., et al.
(author)
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ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients
- 2016
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In: Journal of the European Academy of Dermatology and Venereology. - : Wiley. - 0926-9959. ; 30:5, s. 729-747
-
Journal article (peer-reviewed)abstract
- Atopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease of children and adults. The diagnosis is made using evaluated clinical criteria. Disease activity is best measured with a composite score assessing both objective signs and subjective symptoms, such as SCORAD. The management of AD must consider the clinical and pathogenic variabilities of the disease and also target flare prevention. Basic therapy includes hydrating topical treatment, as well as avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment of visible skin lesions is based on topical glucocorticosteroids and the topical calcineurin inhibitors tacrolimus and pimecrolimus. Topical calcineurin inhibitors are preferred in sensitive locations. Tacrolimus and mid-potent steroids are proven for proactive therapy, which is long-term intermittent anti-inflammatory therapy of the frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is indicated for severe refractory cases. Biologicals targeting key mechanisms of the atopic immune response are promising emerging treatment options. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) may diminish pruritus, but do not have sufficient effect on lesions. Adjuvant therapy includes UV irradiation, preferably UVA1 or narrow-band UVB 311 nm. Dietary recommendations should be patient specific and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. 'Eczema school' educational programmes have been proven to be helpful for children and adults.
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