HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers

Amplification and oncogenic mutations of ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADCs) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2/HER2-amplified or mutant lung cancers. We show that co-treatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy

Risk factors and prognosis of young stroke. The FUTURE study: A prospective cohort study. Study rationale and protocol

Contains fulltext : 98322.pdf (postprint version ) (Open Access)BACKGROUND: Young stroke can have devastating consequences with respect to quality of life, the ability to work, plan or run a family, and participate in social life. Better insight into risk factors and the long-term prognosis is extremely important, especially in young stroke patients with a life expectancy of decades. To date, detailed information on risk factors and the long-term prognosis in young stroke patients, and more specific risk of mortality or recurrent vascular events, remains scarce. METHODS/DESIGN: The FUTURE study is a prospective cohort study on risk factors and prognosis of young ischemic and hemorrhagic stroke among 1006 patients, aged 18-50 years, included in our study database between 1-1-1980 and 1-11-2010. Follow-up visits at our research centre take place from the end of 2009 until the end of 2011. Control subjects will be recruited among the patients' spouses, relatives or social environment. Information on mortality and incident vascular events will be retrieved via structured questionnaires. In addition, participants are invited to the research centre to undergo an extensive sub study including MRI. DISCUSSION: The FUTURE study has the potential to make an important contribution to increase the knowledge on risk factors and long-term prognosis in young stroke patients. Our study differs from previous studies by having a maximal follow-up of more than 30 years, including not only TIA and ischemic stroke but also hemorrhagic stroke, the addition of healthy controls and prospectively collect data during an extensive follow-up visit. Completion of the FUTURE study may provide better information for treating physicians and patients with respect to the prognosis of young stroke.8 p

Detection of cosmic structures using the bispectrum phase. II. First results from application to cosmic reionization using the Hydrogen Epoch of Reionization Array

Characterizing the epoch of reionization (EoR) at $z\gtrsim 6$ via the redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR HI fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the IGM brightness temperature. From this limited data, at $z=7.7$ we infer "$1\sigma$" upper limits on the IGM brightness temperature to be $\le 316$ "pseudo" mK at $\kappa_\parallel=0.33\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (data-limited) and $\le 1000$ "pseudo" mK at $\kappa_\parallel=0.875\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (noise-limited). The "pseudo" units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic HI signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at $\gtrsim 10^6$ dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues

Detection of cosmic structures using the bispectrum phase. II. First results from application to cosmic reionization using the Hydrogen Epoch of Reionization Array

Characterizing the epoch of reionization (EoR) at $z\gtrsim 6$ via the redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR HI fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the IGM brightness temperature. From this limited data, at $z=7.7$ we infer "$1\sigma$" upper limits on the IGM brightness temperature to be $\le 316$ "pseudo" mK at $\kappa_\parallel=0.33\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (data-limited) and $\le 1000$ "pseudo" mK at $\kappa_\parallel=0.875\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (noise-limited). The "pseudo" units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic HI signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at $\gtrsim 10^6$ dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues

Imaging and Modeling Data from the Hydrogen Epoch of Reionization Array

We analyze data from the Hydrogen Epoch of Reionization Array. This is the third in a series of papers on the closure phase delay-spectrum technique designed to detect the HI 21cm emission from cosmic reionization. We present the details of the data and models employed in the power spectral analysis, and discuss limitations to the process. We compare images and visibility spectra made with HERA data, to parallel quantities generated from sky models based on the GLEAM survey, incorporating the HERA telescope model. We find reasonable agreement between images made from HERA data, with those generated from the models, down to the confusion level. For the visibility spectra, there is broad agreement between model and data across the full band of $\sim 80$MHz. However, models with only GLEAM sources do not reproduce a roughly sinusoidal spectral structure at the tens of percent level seen in the observed visibility spectra on scales $\sim 10$ MHz on 29 m baselines. We find that this structure is likely due to diffuse Galactic emission, predominantly the Galactic plane, filling the far sidelobes of the antenna primary beam. We show that our current knowledge of the frequency dependence of the diffuse sky radio emission, and the primary beam at large zenith angles, is inadequate to provide an accurate reproduction of the diffuse structure in the models. We discuss implications due to this missing structure in the models, including calibration, and in the search for the HI 21cm signal, as well as possible mitigation techniques

Understanding the HERA Phase i receiver system with simulations and its impact on the detectability of the EoR delay power spectrum

The detection of the Epoch of Reionization (EoR) delay power spectrum using a "foreground avoidance method" highly depends on the instrument chromaticity. The systematic effects induced by the radio-telescope spread the foreground signal in the delay domain, which contaminates the EoR window theoretically observable. Applied to the Hydrogen Epoch of Reionization Array (HERA), this paper combines detailed electromagnetic and electrical simulations in order to model the chromatic effects of the instrument, and quantify its frequency and time responses. In particular, the effects of the analogue receiver, transmission cables, and mutual coupling are included. These simulations are able to accurately predict the intensity of the reflections occurring in the 150-m cable which links the antenna to the back-end. They also show that electromagnetic waves can propagate from one dish to another one through large sections of the array due to mutual coupling. The simulated system time response is attenuated by a factor $10^{4}$ after a characteristic delay which depends on the size of the array and on the antenna position. Ultimately, the system response is attenuated by a factor $10^{5}$ after 1400 ns because of the reflections in the cable, which corresponds to characterizable ${k_\parallel}$-modes above 0.7 $h\;\rm{Mpc}^{-1}$ at 150 MHz. Thus, this new study shows that the detection of the EoR signal with HERA Phase I will be more challenging than expected. On the other hand, it improves our understanding of the telescope, which is essential to mitigate the instrument chromaticity

Automated Detection of Antenna Malfunctions in Large-N Interferometers: A case study With the Hydrogen Epoch of Reionization Array

We present a framework for identifying and flagging malfunctioning antennas in large radio interferometers. We outline two distinct categories of metrics designed to detect outliers along known failure modes of large arrays: cross-correlation metrics, based on all antenna pairs, and auto-correlation metrics, based solely on individual antennas. We define and motivate the statistical framework for all metrics used, and present tailored visualizations that aid us in clearly identifying new and existing systematics. We implement these techniques using data from 105 antennas in the Hydrogen Epoch of Reionization Array (HERA) as a case study. Finally, we provide a detailed algorithm for implementing these metrics as flagging tools on real data sets

Foreground modelling via Gaussian process regression: An application to HERA data

The key challenge in the observation of the redshifted 21-cm signal from cosmic reionization is its separation from the much brighter foreground emission. Such separation relies on the different spectral properties of the two components, although, in real life, the foreground intrinsic spectrum is often corrupted by the instrumental response, inducing systematic effects that can further jeopardize the measurement of the 21-cm signal. In this paper, we use Gaussian Process Regression to model both foreground emission and instrumental systematics in $\sim 2$ hours of data from the Hydrogen Epoch of Reionization Array. We find that a simple co-variance model with three components matches the data well, giving a residual power spectrum with white noise properties. These consist of an "intrinsic" and instrumentally corrupted component with a coherence-scale of 20 MHz and 2.4 MHz respectively (dominating the line of sight power spectrum over scales $k_{\parallel} \le 0.2$ h cMpc$^{-1}$) and a baseline dependent periodic signal with a period of $\sim 1$ MHz (dominating over $k_{\parallel} \sim 0.4 - 0.8$h cMpc$^{-1}$) which should be distinguishable from the 21-cm EoR signal whose typical coherence-scales is $\sim 0.8$ MHz

Foreground modelling via Gaussian process regression: An application to HERA data

The key challenge in the observation of the redshifted 21-cm signal from cosmic reionization is its separation from the much brighter foreground emission. Such separation relies on the different spectral properties of the two components, although, in real life, the foreground intrinsic spectrum is often corrupted by the instrumental response, inducing systematic effects that can further jeopardize the measurement of the 21-cm signal. In this paper, we use Gaussian Process Regression to model both foreground emission and instrumental systematics in $\sim 2$ hours of data from the Hydrogen Epoch of Reionization Array. We find that a simple co-variance model with three components matches the data well, giving a residual power spectrum with white noise properties. These consist of an "intrinsic" and instrumentally corrupted component with a coherence-scale of 20 MHz and 2.4 MHz respectively (dominating the line of sight power spectrum over scales $k_{\parallel} \le 0.2$ h cMpc$^{-1}$) and a baseline dependent periodic signal with a period of $\sim 1$ MHz (dominating over $k_{\parallel} \sim 0.4 - 0.8$h cMpc$^{-1}$) which should be distinguishable from the 21-cm EoR signal whose typical coherence-scales is $\sim 0.8$ MHz