NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer

Alternative splicing is dysregulated in cancer and the reactivation of telomerase involves the splicing of TERT transcripts to produce full-length (FL) TERT. Knowledge about the splicing factors that enhance or silence FL hTERT is lacking. We identified splicing factors that reduced telomerase activity and shortened telomeres using a siRNA minigene reporter screen and a lung cancer cell bioinformatics approach. A lead candidate, NOVA1, when knocked down resulted in a shift in hTERT splicing to non-catalytic isoforms, reduced telomerase activity, and progressive telomere shortening. NOVA1 knockdown also significantly altered cancer cell growth in vitro and in xenografts. Genome engineering experiments reveal that NOVA1 promotes the inclusion of exons in the reverse transcriptase domain of hTERT resulting in the production of FL hTERT transcripts. Utilizing hTERT splicing as a model splicing event in cancer may provide new insights into potentially targetable dysregulated splicing factors in cancer

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.Canadian Institutes of Health Research [MOP 82727]info:eu-repo/semantics/publishedVersio

First detection of VHE gamma-ray emission from TXS 1515-273, study of its X-ray variability and spectral energy distribution

We report here on the first multi-wavelength (MWL) campaign on the blazar TXS 1515-273, undertaken in 2019 and extending from radio to very-high-energy gamma rays (VHE). Up until now, this blazar had not been the subject of any detailed MWL observations. It has a rather hard photon index at GeV energies and was considered a candidate extreme high-synchrotronpeaked source. MAGIC observations resulted in the first-time detection of the source in VHE with a statistical significance of 7.6$\sigma$. The average integral VHE flux of the source is 6 $\pm$ 1% of the Crab nebula flux above 400 GeV. X-ray coverage was provided by Swift-XRT, XMMNewton, and NuSTAR. The long continuous X-ray observations were separated by $\sim$ 9 h, both showing clear hour scale flares. In the XMM-Newton data, both the rise and decay timescales are longer in the soft X-ray than in the hard X-ray band, indicating the presence of a particle cooling regime. The X-ray variability timescales were used to constrain the size of the emission region and the strength of the magnetic field. The data allowed us to determine the synchrotron peak frequency and classify the source as a flaring high, but not extreme, synchrotron peaked object. Considering the constraints and variability patterns from the X-ray data, we model the broad-band spectral energy distribution. We applied a simple one-zone model, which could not reproduce the radio emission and the shape of the optical emission, and a two-component leptonic model with two interacting components, enabling us to reproduce the emission from radio to VHE band

Study of the GeV to TeV morphology of the γ Cygni SNR (G 78.2+2.1) with MAGIC and Fermi-LAT: Evidence for cosmic ray escape

Context. Diffusive shock acceleration (DSA) is the most promising mechanism that accelerates Galactic cosmic rays (CRs) in the shocks of supernova remnants (SNRs). It is based on particles scattering caused by turbulence ahead and behind the shock. The turbulence upstream is supposedly generated by the CRs, but this process is not well understood. The dominant mechanism may depend on the evolutionary state of the shock and can be studied via the CRs escaping upstream into the interstellar medium (ISM). Aims. Previous observations of the γ Cygni SNR showed a difference in morphology between GeV and TeV energies. Since this SNR has the right age and is at the evolutionary stage for a significant fraction of CRs to escape, our aim is to understand γ-ray emission in the vicinity of the γ Cygni SNR. Methods. We observed the region of the γ Cygni SNR with the MAGIC Imaging Atmospheric Cherenkov telescopes between 2015 May and 2017 September recording 87 h of good-quality data. Additionally, we analysed Fermi-LAT data to study the energy dependence of the morphology as well as the energy spectrum in the GeV to TeV range. The energy spectra and morphology were compared against theoretical predictions, which include a detailed derivation of the CR escape process and their γ-ray generation. Results. The MAGIC and Fermi-LAT data allowed us to identify three emission regions that can be associated with the SNR and that dominate at different energies. Our hadronic emission model accounts well for the morphology and energy spectrum of all source components. It constrains the time-dependence of the maximum energy of the CRs at the shock, the time-dependence of the level of turbulence, and the diffusion coefficient immediately outside the SNR shock. While in agreement with the standard picture of DSA, the time-dependence of the maximum energy was found to be steeper than predicted, and the level of turbulence was found to change over the lifetime of the SNR. © 2023 EDP Sciences. All rights reserved

Prevalence of thyroid disorders and thyroid autoantibodies among coastal communities of Malaysia (part of nationwide study of thyroid disorders in Malaysia)

Objectives To determine the prevalence of thyroid disorders and thyroid autoantibodies in the coastal communities of Malaysia. This study is part of a nationwide study looking into the prevalence of thyroid disorders. Methods A cross sectional study was performed in two coastal districts of rural Selangor. A village from each district was chosen where a participant from each household from the village was selected using KISH tables. Sociodemographic data, medical history, anthropometric measurement and thyroid examination were performed. The presence of goiter was recorded according to the World Health Organization (WHO) goiter grading system. Blood withdrawn was tested for thyroid function and thyroid autoantibodies. Thyroid antibodies analyses were done using Immulite 2000 system. Lowest detectable limit for anti-thyroperoxidase (antiTPO) and antithyroglobulin (antiTG) are 10 IU/mL and 20 IU/mL respectively. Low, moderate and high titre is defined 40 - 100 IU/mL, 101-1000 IU/mL and >1000 IU/mL respectively. Results A total of 418 subjects were recruited with a mean age of 54.1 ± 14.2 years. Majority were Malays (86.8%), followed by Indians (11.7%) and Chinese (1.4%). Among respondents, 2.9% had Grade 1 and 8.9% had Grade 2 goitre. A mere 3.4% had clinically palpable thyroid nodules. A total of 411 blood samples were available for thyroid level assessment, with 1.9% of respondents were found to have hypothyroidism while 85.6% had TSH in the range of 0.32-2.5 mIU/L. The prevalence of overt and subclinical hypothyroidism was 0.2% and 1.7% AFES 2015 10 – 13 December 2015 respectively. On the otherhand, 3.4% of respondents were hyperthyroid (TSH < 0.32 mIU/L) with prevalence of overt and subclinical hyperthyroidism being 0.5% and 2.9% respectively. Among 417 samples which were available for antiTPO analysis, 8.9% has detectable antiTPO titre (>40.0 IU/mL), with 4.3% had moderate and 2.4% had high antiTPO titres. One respondent (10%) from among those with high antiTPO titres was found to have T3 thyrotoxicosis. Fourty percent of euthyroid respondents with high titre and 38.9% with moderate titre had high normal TSH, in the range of 2.51 – 5.00 mIU/L (p<0.001). Among 417 samples which are available for antiTG analysis, 3.4% and 5.3% had low detectable and moderate antiTG titres respectively. Only 0.5% (2 respondents) had high antiTG titre (>1000 IU/mL) and found to be hypothyroid. Among those with moderately positive titre, 9.1% were hyperthyroid and majority (63.6%), although euthyroid, had TSH levels between 0.32 – 2.50 mIU/L (p<0.001). Conclusion The low prevalence of thyroid antibodies and thyroid disorders in coastal communities could be attributed to the iodine sufficient status in those areas. Euthyroid respondents with moderate and high antiTPO titres tend to have higher TSH levels, while those with moderate and high antiTG titres had lower TSH levels

Multi-year characterisation of the broad-band emission from the intermittent extreme BL Lac 1ES~2344+514

The BL Lac 1ES 2344+514 is known for temporary extreme properties (e.g., a shift of the synchrotron SED peak energy $\nu_{synch,p}$ above 1keV). While those extreme states were so far observed only during high flux levels, additional multi-year observing campaigns are required to achieve a coherent picture. Here, we report the longest investigation of the source from radio to VHE performed so far, focusing on a systematic characterisation of the intermittent extreme states. While our results confirm that 1ES 2344+514 typically exhibits $\nu_{synch,p}>$1keV during elevated flux periods, we also find periods where the extreme state coincides with low flux activity. A strong spectral variability thus happens in the quiescent state, and is likely caused by an increase of the electron acceleration efficiency without a change in the electron injection luminosity. We also report a strong X-ray flare (among the brightest for 1ES 2344+514) without a significant shift of $\nu_{synch,p}$. During this particular flare, the X-ray spectrum is among the softest of the campaign. It unveils complexity in the spectral evolution, where the common harder-when-brighter trend observed in BL Lacs is violated. During a low and hard X-ray state, we find an excess of the UV flux with respect to an extrapolation of the X-ray spectrum to lower energies. This UV excess implies that at least two regions contribute significantly to the infrared/optical/ultraviolet/X-ray emission. Using the simultaneous MAGIC, XMM-Newton, NuSTAR, and AstroSat observations, we argue that a region possibly associated with the 10 GHz radio core may explain such an excess. Finally, we investigate a VHE flare, showing an absence of simultaneous variability in the 0.3-2keV band. Using a time-dependent leptonic modelling, we show that this behaviour, in contradiction to single-zone scenarios, can instead be explained by a two-component model.Comment: Accepted for publication in Astronomy & Astrophysic

Long-term multi-wavelength study of 1ES 0647+250

The BL Lac object 1ES 0647+250 is one of the few distant $\gamma$-ray emitting blazars detected at very high energies (VHE, $\gtrsim$100 GeV) during a non-flaring state. It was detected with the MAGIC telescopes during its low activity in the years 2009-2011, as well as during three flaring activities in the years 2014, 2019 and 2020, with the highest VHE flux in the latter epoch. An extensive multi-instrument data set was collected within several coordinated observing campaigns throughout these years. We aim to characterise the long-term multi-band flux variability of 1ES 0647+250, as well as its broadband spectral energy distribution (SED) during four distinct activity states selected in four different epochs, in order to constrain the physical parameters of the blazar emission region under certain assumptions. We evaluate the variability and correlation of the emission in the different energy bands with the fractional variability and the Z-transformed Discrete Correlation Function, as well as its spectral evolution in X-rays and $\gamma$ rays. Owing to the controversy in the redshift measurements of 1ES 0647+250 reported in the literature, we also estimate its distance in an indirect manner through the comparison of the GeV and TeV spectra from simultaneous observations with Fermi-LAT and MAGIC during the strongest flaring activity detected to date. Moreover, we interpret the SEDs from the four distinct activity states within the framework of one-component and two-component leptonic models, proposing specific scenarios that are able to reproduce the available multi-instrument data.Comment: 20 pages, 7 figures. Accepted in A&A. Corresponding authors: Jorge Otero-Santos; Daniel Morcuende; Vandad Fallah Ramazani; Daniela Dorner; David Paneque (mailto: [email protected]

MAGIC observations provide compelling evidence of hadronic multi-TeV emission from the putative PeVatron SNR G106.3+2.7

Context. Certain types of supernova remnants (SNRs) in our Galaxy are assumed to be PeVatrons, capable of accelerating cosmic rays (CRs) to ∼ PeV energies. However, conclusive observational evidence for this has not yet been found. The SNR G106.3+2.7, detected at 1- 100 TeV energies by different γ-ray facilities, is one of the most promising PeVatron candidates. This SNR has a cometary shape, which can be divided into a head and a tail region with different physical conditions. However, in which region the 100 TeV emission is produced has not yet been identified because of the limited position accuracy and/or angular resolution of existing observational data. Additionally, it remains unclear as to whether the origin of the γ-ray emission is leptonic or hadronic. Aims. With the better angular resolution provided by new MAGIC data compared to earlier γ-ray datasets, we aim to reveal the acceleration site of PeV particles and the emission mechanism by resolving the SNR G106.3+2.7 with 0.1 resolution at TeV energies. Methods. We observed the SNR G106.3+2.7 using the MAGIC telescopes for 121.7 h in total - after quality cuts - between May 2017 and August 2019. The analysis energy threshold is ∼0.2 TeV, and the angular resolution is 0.07-0.1. We examined the γ-ray spectra of different parts of the emission, whilst benefitting from the unprecedented statistics and angular resolution at these energies provided by our new data. We also used measurements at other wavelengths such as radio, X-rays, GeV γ-rays, and 10 TeV γ-rays to model the emission mechanism precisely. Results. We detect extended γ-ray emission spatially coincident with the radio continuum emission at the head and tail of SNR G106.3+2.7. The fact that we detect a significant γ-ray emission with energies above 6.0 TeV from only the tail region suggests that the emissions above 10 TeV detected with air shower experiments (Milagro, HAWC, Tibet ASγ and LHAASO) are emitted only from the SNR tail. Under this assumption, the multi-wavelength spectrum of the head region can be explained with either hadronic or leptonic models, while the leptonic model for the tail region is in contradiction with the emission above 10 TeV and X-rays. In contrast, the hadronic model could reproduce the observed spectrum at the tail by assuming a proton spectrum with a cutoff energy of ∼1 PeV for that region. Such high-energy emission in this middle-aged SNR (4-10 kyr) can be explained by considering a scenario where protons escaping from the SNR in the past interact with surrounding dense gases at present. Conclusions. The γ-ray emission region detected with the MAGIC telescopes in the SNR G106.3+2.7 is extended and spatially coincident with the radio continuum morphology. The multi-wavelength spectrum of the emission from the tail region suggests proton acceleration up to ∼PeV, while the emission mechanism of the head region could either be hadronic or leptonic

MAGIC observations provide compelling evidence of the hadronic multi-TeV emission from the putative PeVatron SNR G106.3+2.7

The SNR G106.3+2.7, detected at 1--100 TeV energies by different $\gamma$-ray facilities, is one of the most promising PeVatron candidates. This SNR has a cometary shape which can be divided into a head and a tail region with different physical conditions. However, it is not identified in which region the 100 TeV emission is produced due to the limited position accuracy and/or angular resolution of existing observational data. Additionally, it remains unclear whether the origin of the $\gamma$-ray emission is leptonic or hadronic. With the better angular resolution provided by these new MAGIC data compared to earlier $\gamma$-ray datasets, we aim to reveal the acceleration site of PeV particles and the emission mechanism by resolving the SNR G106.3+2.7 with 0.1$^\circ$ resolution at TeV energies. We detected extended $\gamma$-ray emission spatially coincident with the radio continuum emission at the head and tail of SNR G106.3+2.7. The fact that we detected a significant $\gamma$-ray emission with energies above 6.0 TeV from the tail region only suggests that the emissions above 10 TeV, detected with air shower experiments (Milagro, HAWC, Tibet AS$\gamma$ and LHAASO), are emitted only from the SNR tail. Under this assumption, the multi-wavelength spectrum of the head region can be explained with either hadronic or leptonic models, while the leptonic model for the tail region is in contradiction with the emission above 10 TeV and X-rays. In contrast, the hadronic model could reproduce the observed spectrum at the tail by assuming a proton spectrum with a cutoff energy of $\sim 1$ PeV for the tail region. Such a high energy emission in this middle-aged SNR (4--10 kyr) can be explained by considering the scenario that protons escaping from the SNR in the past interact with surrounding dense gases at present.Comment: 13 pages, 7 figures, Accepted for publication in A&