Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer

Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer

Health care utilisation under the 30-Baht Scheme among the urban poor in Mitrapap slum, Khon Kaen, Thailand: a cross-sectional study

Background: In 2001, the Government of Thailand introduced a universal coverage scheme with the aim of ensuring equitable health care access for even the poorest citizens. For a flat user fee of 30 Baht per consultation, or for free for those falling into exemption categories, every scheme participant may access registered health services. The exemption categories include children under 12 years of age, senior citizens aged 60 years and over, the very poor, and volunteer health workers. The functioning of these exemption mechanisms and the effect of the scheme on health service utilisation among the poor is controversial. Methods: This cross-sectional study investigated the prevalence of 30-Baht Scheme registration and subsequent self-reported health service utilisation among an urban poor population in the Teparuk community within the Mitrapap slum in Khon Kaen city, northeastern Thailand. Furthermore, the effectiveness of the exemption mechanisms in reaching the very poor and the elderly was examined. Factors for users' choice of health facilities were identified. Results: Overall, the proportion of the Teparuk community enrolled with the 30-Baht Scheme was high at 86%, with over one quarter of these exempted from paying the consultation fee. User fee exemption was significantly more frequent among households with an above-poverty-line income (64.7%) compared to those below the poverty line (35.3%), χ2 (df) = 5.251 (1); p-value = 0.018. In addition, one third of respondents over 60 years of age were found to be still paying user fees. Self-reported use of registered medical facilities in case of illness was stated to be predominantly due to the service being available through the scheme, with service quality not a chief consideration. Overall consumer satisfaction was high, especially among those not required to pay the 30 Baht user fee. Conclusion: Whilst the 30-Baht Scheme seems to cover most of the poor population of Mitrapap slum in Khon Kaen, the user fee exemption mechanism only works partially with regard to reaching the poorest and exempting senior citizens. Service utilisation and satisfaction are highest amongst those who are fee-exempt. Service quality was not an important factor influencing choice of health facility. Ways should be sought to improve the effectiveness of the current exemption mechanisms.Sophie Coronini-Cronberg, Wongsa Laohasiriwong and Christian A Gerick

Measurement of atmospheric neutrino mixing with improved IceCube DeepCore calibration and data processing

We describe a new data sample of IceCube DeepCore and report on the latest measurement of atmospheric neutrino oscillations obtained with data recorded between 2011–2019. The sample includes significant improvements in data calibration, detector simulation, and data processing, and the analysis benefits from a sophisticated treatment of systematic uncertainties, with significantly greater level of detail since our last study. By measuring the relative fluxes of neutrino flavors as a function of their reconstructed energies and arrival directions we constrain the atmospheric neutrino mixing parameters to be sin2θ23=0.51±0.05 and Δm232=2.41±0.07×10−3  eV2, assuming a normal mass ordering. The errors include both statistical and systematic uncertainties. The resulting 40% reduction in the error of both parameters with respect to our previous result makes this the most precise measurement of oscillation parameters using atmospheric neutrinos. Our results are also compatible and complementary to those obtained using neutrino beams from accelerators, which are obtained at lower neutrino energies and are subject to different sources of uncertainties

Search for Extended Sources of Neutrino Emission in the Galactic Plane with IceCube

The Galactic plane, harboring a diffuse neutrino flux, is a particularly interesting target to study potential cosmic-ray acceleration sites. Recent gamma-ray observations by HAWC and LHAASO have presented evidence for multiple Galactic sources that exhibit a spatially extended morphology and have energy spectra continuing beyond 100 TeV. A fraction of such emission could be produced by interactions of accelerated hadronic cosmic rays, resulting in an excess of high-energy neutrinos clustered near these regions. Using 10 years of IceCube data comprising track-like events that originate from charged-current muon neutrino interactions, we perform a dedicated search for extended neutrino sources in the Galaxy. We find no evidence for time-integrated neutrino emission from the potential extended sources studied in the Galactic plane. The most significant location, at 2.6$\sigma$ post-trials, is a 1.7$^\circ$ sized region coincident with the unidentified TeV gamma-ray source 3HWC J1951+266. We provide strong constraints on hadronic emission from several regions in the Galaxy.Comment: 13 pages, 4 figures, 5 tables including an appendix. Accepted for publication in Astrophysical Journa

Measurement of Atmospheric Neutrino Mixing with Improved IceCube DeepCore Calibration and Data Processing

We describe a new data sample of IceCube DeepCore and report on the latest measurement of atmospheric neutrino oscillations obtained with data recorded between 2011-2019. The sample includes significant improvements in data calibration, detector simulation, and data processing, and the analysis benefits from a detailed treatment of systematic uncertainties, with significantly higher level of detail since our last study. By measuring the relative fluxes of neutrino flavors as a function of their reconstructed energies and arrival directions we constrain the atmospheric neutrino mixing parameters to be $\sin^2\theta_{23} = 0.51\pm 0.05$ and $\Delta m^2_{32} = 2.41\pm0.07\times 10^{-3}\mathrm{eV}^2$, assuming a normal mass ordering. The resulting 40\% reduction in the error of both parameters with respect to our previous result makes this the most precise measurement of oscillation parameters using atmospheric neutrinos. Our results are also compatible and complementary to those obtained using neutrino beams from accelerators, which are obtained at lower neutrino energies and are subject to different sources of uncertainties

IceCat-1: The IceCube Event Catalog of Alert Tracks

We present a catalog of likely astrophysical neutrino track-like events from the IceCube Neutrino Observatory. IceCube began reporting likely astrophysical neutrinos in 2016, and this system was updated in 2019. The catalog presented here includes events that were reported in real time since 2019, as well as events identified in archival data samples starting from 2011. We report 275 neutrino events from two selection channels as the first entries in the catalog, the IceCube Event Catalog of Alert Tracks, which will see ongoing extensions with additional alerts. The Gold and Bronze alert channels respectively provide neutrino candidates with a 50% and 30% probability of being astrophysical, on average assuming an astrophysical neutrino power-law energy spectral index of 2.19. For each neutrino alert, we provide the reconstructed energy, direction, false-alarm rate, probability of being astrophysical in origin, and likelihood contours describing the spatial uncertainty in the alert\u27s reconstructed location. We also investigate a directional correlation of these neutrino events with gamma-ray and X-ray catalogs, including 4FGL, 3HWC, TeVCat, and Swift-BAT