Inhibition of Epidermal Growth Factor Receptor and PI3K/Akt Signaling Suppresses Cell Proliferation and Survival through Regulation of Stat3 Activation in Human Cutaneous Squamous Cell Carcinoma

Recent studies have emphasized the important role of Stat3 activation in a number of human tumors from the viewpoint of its oncogenic and antiapoptotic activity. In this study, we examined the role and related signaling molecules of Stat3 in the carcinogenesis of human cutaneous squamous cell carcinoma (SCC). In 35 human cutaneous SCC samples, 86% showed overexpression of phosphorylated (p)-Stat3, and most of those simultaneously overexpressed p-EGFR or p-Akt. Constitutive activation of EGFR and Stat3 was observed in three SCC cell lines and four of five SCC tissues. AG1478, an inhibitor of the EGFR, downregulated Stat3 activation in HSC-1 human SCC cells. AG1478 inhibited cell proliferation and induced apoptosis of HSC-1 cells but did not inhibit the growth of normal human epidermal keratinocytes that did not show Stat3 activation. Furthermore, a PI3K inhibitor also suppressed Stat3 activation in HSC-1 cells to some degree. Combined treatment with the PI3K inhibitor and AG1478 strongly suppressed Stat3 activity and dramatically induced apoptosis of HSC-1 cells. These data suggest that Stat3 activation through EGFR and/or PI3K/Akt activation plays a critical role in the proliferation and survival of human cutaneous SCC

Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

CAR-T細胞製造を成功させるためのレシピ --アフェレーシス前の下ごしらえでの工夫--. 京都大学プレスリリース. 2023-04-27.For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10⁴/μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (<one third) (OR, 3.249; p = 0.011) in peripheral blood at apheresis increased the risk of manufacturing failure. Manufacturing failure remains an obstacle to CAR-T cell therapy for DLBCL patients. Avoiding risk factors, such as repeated bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients

Mechanical design of the optical modules intended for IceCube-Gen2

IceCube-Gen2 is an expansion of the IceCube neutrino observatory at the South Pole that aims to increase the sensitivity to high-energy neutrinos by an order of magnitude. To this end, about 10,000 new optical modules will be installed, instrumenting a fiducial volume of about 8 km3. Two newly developed optical module types increase IceCube’s current sensitivity per module by a factor of three by integrating 16 and 18 newly developed four-inch PMTs in specially designed 12.5-inch diameter pressure vessels. Both designs use conical silicone gel pads to optically couple the PMTs to the pressure vessel to increase photon collection efficiency. The outside portion of gel pads are pre-cast onto each PMT prior to integration, while the interiors are filled and cast after the PMT assemblies are installed in the pressure vessel via a pushing mechanism. This paper presents both the mechanical design, as well as the performance of prototype modules at high pressure (70 MPa) and low temperature (−40∘C), characteristic of the environment inside the South Pole ice

The next generation neutrino telescope: IceCube-Gen2

The IceCube Neutrino Observatory, a cubic-kilometer-scale neutrino detector at the geographic South Pole, has reached a number of milestones in the field of neutrino astrophysics: the discovery of a high-energy astrophysical neutrino flux, the temporal and directional correlation of neutrinos with a flaring blazar, and a steady emission of neutrinos from the direction of an active galaxy of a Seyfert II type and the Milky Way. The next generation neutrino telescope, IceCube-Gen2, currently under development, will consist of three essential components: an array of about 10,000 optical sensors, embedded within approximately 8 cubic kilometers of ice, for detecting neutrinos with energies of TeV and above, with a sensitivity five times greater than that of IceCube; a surface array with scintillation panels and radio antennas targeting air showers; and buried radio antennas distributed over an area of more than 400 square kilometers to significantly enhance the sensitivity of detecting neutrino sources beyond EeV. This contribution describes the design and status of IceCube-Gen2 and discusses the expected sensitivity from the simulations of the optical, surface, and radio components

Sensitivity of IceCube-Gen2 to measure flavor composition of Astrophysical neutrinos

The observation of an astrophysical neutrino flux in IceCube and its detection capability to separate between the different neutrino flavors has led IceCube to constraint the flavor content of this flux. IceCube-Gen2 is the planned extension of the current IceCube detector, which will be about 8 times larger than the current instrumented volume. In this work, we study the sensitivity of IceCube-Gen2 to the astrophysical neutrino flavor composition and investigate its tau neutrino identification capabilities. We apply the IceCube analysis on a simulated IceCube-Gen2 dataset that mimics the High Energy Starting Event (HESE) classification. Reconstructions are performed using sensors that have 3 times higher quantum efficiency and isotropic angular acceptance compared to the current IceCube optical modules. We present the projected sensitivity for 10 years of data on constraining the flavor ratio of the astrophysical neutrino flux at Earth by IceCube-Gen2

Direction reconstruction performance for IceCube-Gen2 Radio

The IceCube-Gen2 facility will extend the energy range of IceCube to ultra-high energies. The key component to detect neutrinos with energies above 10 PeV is a large array of in-ice radio detectors. In previous work, direction reconstruction algorithms using the forward-folding technique have been developed for both shallow (≲20 m) and deep in-ice detectors, and have also been successfully used to reconstruct cosmic rays with ARIANNA. Here, we focus on the reconstruction algorithm for the deep in-ice detector, which was recently introduced in the context of the Radio Neutrino Observatory in Greenland (RNO-G)

Estimating the coincidence rate between the optical and radio array of IceCube-Gen2

The IceCube-Gen2 Neutrino Observatory is proposed to extend the all-flavour energy range of IceCube beyond PeV energies. It will comprise two key components: I) An enlarged 8km3 in-ice optical Cherenkov array to measure the continuation of the IceCube astrophysical neutrino flux and improve IceCube\u27s point source sensitivity above ∼100TeV; and II) A very large in-ice radio array with a surface area of about 500km2. Radio waves propagate through ice with a kilometer-long attenuation length, hence a sparse radio array allows us to instrument a huge volume of ice to achieve a sufficient sensitivity to detect neutrinos with energies above tens of PeV. The different signal topologies for neutrino-induced events measured by the optical and in-ice radio detector - the radio detector is mostly sensitive to the cascades produced in the neutrino interaction, while the optical detector can detect long-ranging muon and tau leptons with high accuracy - yield highly complementary information. When detected in coincidence, these signals will allow us to reconstruct the neutrino energy and arrival direction with high fidelity. Furthermore, if events are detected in coincidence with a sufficient rate, they resemble the unique opportunity to study systematic uncertainties and to cross-calibrate both detector components

Deep Learning Based Event Reconstruction for the IceCube-Gen2 Radio Detector

The planned in-ice radio array of IceCube-Gen2 at the South Pole will provide unprecedented sensitivity to ultra-high-energy (UHE) neutrinos in the EeV range. The ability of the detector to measure the neutrino’s energy and direction is of crucial importance. This contribution presents an end-to-end reconstruction of both of these quantities for both detector components of the hybrid radio array (\u27shallow\u27 and \u27deep\u27) using deep neural networks (DNNs). We are able to predict the neutrino\u27s direction and energy precisely for all event topologies, including the electron neutrino charged-current (νe-CC) interactions, which are more complex due to the LPM effect. This highlights the advantages of DNNs for modeling the complex correlations in radio detector data, thereby enabling a measurement of the neutrino energy and direction. We discuss how we can use normalizing flows to predict the PDF for each individual event which allows modeling the complex non-Gaussian uncertainty contours of the reconstructed neutrino direction. Finally, we discuss how this work can be used to further optimize the detector layout to improve its reconstruction performance

Sensitivity of the IceCube-Gen2 Surface Array for Cosmic-Ray Anisotropy Studies

The energy of the transition from Galactic to extra-galactic origin of cosmic rays is one of the major unresolved issues of cosmic-ray physics. However, strong constraints can be obtained from studying the anisotropy in the arrival directions of cosmic rays. The sensitivity to cosmic-ray anisotropy is, in particular, a matter of statistics. Recently, the cosmic ray anisotropy measurements in the TeV to PeV energy range were updated from IceCube using 11 years of data. The IceCube-Gen2 surface array will cover an area about 8 times larger than the existing IceTop surface array with a corresponding increase in statistics and capability to investigate cosmic-ray anisotropy with higher sensitivity. In this contribution, we present details on the performed simulation studies and sensitivity to the cosmic-ray anisotropy signal for the IceCube-Gen2 surface array