Targeting ErbB-2 nuclear localization and function inhibits breast cancer growth and overcomes trastuzumab resistance

Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.Fil: Cordo Russo, Rosalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Béguelin, W.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Venturutti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Galigniana, Natalia Maricel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Tkach, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Guzmán, P.. Universidad de La Frontera; ChileFil: Roa, J.C.. Universidad de La Frontera; ChileFil: O'Brien, N.A.. David Geffen School of Medicine at UCLA; Estados UnidosFil: Charreau, Eduardo Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

SKYSURF-4: Panchromatic HST All-Sky Surface-Brightness Measurement Methods and Results

The diffuse, unresolved sky provides most of the photons that the Hubble Space Telescope (HST) receives, yet remains poorly understood. HST Archival Legacy program SKYSURF aims to measure the 0.2-1.6 $\mu$m sky surface brightness (sky-SB) from over 140,000 HST images. We describe a sky-SB measurement algorithm designed for SKYSURF that is able to recover the input sky-SB from simulated images to within 1% uncertainty. We present our sky-SB measurements estimated using this algorithm on the entire SKYSURF database. Comparing our sky-SB spectral energy distribution (SED) to measurements from the literature shows general agreements. Our SKYSURF SED also reveals a possible dependence on Sun angle, indicating either non-isotropic scattering of solar photons off interplanetary dust or an additional component to Zodiacal Light. Finally, we update Diffuse Light limits in the near-IR based on the methods from Carleton et al. (2022), with values of 0.009 MJy sr$^{-1}$ (22 nW m$^{-2}$ sr$^{-1}$) at 1.25 $\mu$m, 0.015 MJy sr$^{-1}$ (32 nW m$^{-2}$ sr$^{-1}$) at 1.4 $\mu$m, and 0.013 MJy sr$^{-1}$ (25 nW m$^{-2}$ sr$^{-1}$) at 1.6 $\mu$m. These estimates provide the most stringent all-sky constraints to date in this wavelength range. SKYSURF sky-SB measurements are made public on the official SKYSURF website and will be used to constrain Diffuse Light in future papers.Comment: Revised based on helpful comments from the reviewer, and accepted to AJ on April 12th, 2023. Main paper: 18 pages, 9 figures, 4 tables. Appendices: 16 pages, 10 figures, 1 table. Main results shown in Figure 7 and Table

SKYSURF: Constraints on Zodiacal Light and Extragalactic Background Light through Panchromatic HST All-Sky Surface-Brightness Measurements: I. Survey Overview and Methods

We give an overview and describe the rationale, methods, and testing of the Hubble Space Telescope (HST) Archival Legacy project "SKYSURF." SKYSURF uses HST's unique capability as an absolute photometer to measure the ~0.2-1.7 $\mu$m sky surface brightness (SB) from 249,861 WFPC2, ACS, and WFC3 exposures in ~1400 independent HST fields. SKYSURF's panchromatic dataset is designed to constrain the discrete and diffuse UV to near-IR sky components: Zodiacal Light (ZL; inner Solar System), Kuiper Belt Objects (KBOs; outer Solar System), Diffuse Galactic Light (DGL), and the discrete plus diffuse Extragalactic Background Light (EBL). We outline SKYSURF's methods to: (1) measure sky-SB levels between its detected objects; (2) measure the integrated discrete EBL, most of which comes from AB$\simeq$17-22 mag galaxies; and (3) estimate how much diffuse light may exist in addition to the extrapolated discrete galaxy counts. Simulations of HST WFC3/IR images with known sky-values and gradients, realistic cosmic ray (CR) distributions, and star plus galaxy counts were processed with nine different algorithms to measure the "Lowest Estimated Sky-SB" (LES) in each image between the discrete objects. The best algorithms recover the inserted LES values within 0.2% when there are no image gradients, and within 0.2-0.4% when there are 5-10% gradients. SKYSURF requires non-standard re-processing of these HST images that includes restoring the lowest sky-level from each visit into each drizzled image. We provide a proof of concept of our methods from the WFC3/IR F125W images, where any residual diffuse light that HST sees in excess of the Kelsall et al. (1998) Zodiacal model prediction does not depend on the total object flux that each image contains. This enables us to present our first SKYSURF results on diffuse light in Carleton et al. (2022).Comment: Accepted to AJ; see accompanying paper Carleton et al. 2022: arXiv:2205.06347. Comments welcome

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

SKYSURF: Constraints on Zodiacal Light and Extragalactic Background Light through Panchromatic HST All-Sky Surface-Brightness Measurements: II. First Limits on Diffuse Light at 1.25, 1.4, and 1.6 microns

We present the first results from the HST Archival Legacy project "SKYSURF." As described in Windhorst et al. 2022, SKYSURF utilizes the large HST archive to study the diffuse UV, optical, and near-IR backgrounds and foregrounds in detail. Here we utilize SKYSURF's first sky-surface brightness measurements to constrain the level of near-IR diffuse Extragalactic Background Light (EBL). Our sky-surface brightness measurements have been verified to an accuracy of better than 1%, which when combined with systematic errors associated with HST, results in sky brightness uncertainties of $\sim$2-4% $\simeq$ 0.005 MJy/sr in each image. We put limits on the amount of diffuse EBL in three near-IR filters (F125W, F140W, and F160W) by comparing our preliminary sky measurements of $> 30,000$ images to Zodiacal light models, carefully selecting the darkest images to avoid contamination from stray light. In addition, we investigate the impact that instrumental thermal emission has on our measurements, finding that it has a limited impact on F125W and F140W measurements, whereas uncertainties in the exact thermal state of HST results in significant uncertainties in the level of astrophysical diffuse light in F160W images. When compared to the Kelsall et al. (1998) Zodiacal model, an isotropic diffuse background of $30$ nW m$^{-2}$ sr$^{-1}$ remains, whereas using the Wright (1998) Zodiacal model results in no discernible diffuse background. Based primarily on uncertainties in the foreground model subtraction, we present limits on the amount of diffuse EBL of 29 nW m$^{-2}$ sr$^{-1}$, 40 nW m$^{-2}$ sr$^{-1}$, and 29 nW m$^{-2}$ sr$^{-1}$ for F125W, F140W, and F160W respectively. While this light is generally isotropic, our modeling at this point does not distinguish between a cosmological origin or a Solar System origin (such as a dim, diffuse, spherical cloud of cometary dust).Comment: To be submitted with Windhorst et al. 2022 to AJ. Main figures are Fig. 10 and 11. Comments welcome

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

Explosive growth of nanomedicines continues to significantly impact the therapeutic strategies for effective cancer treatment. Despite the significant progress in the development of advanced nanomedicines, successful clinical translation remains challenging. As cancer nanomedicine is a multidisciplinary field, the fundamental problem is that the knowledge gaps stem from different vantage points in the understanding of cancer nanomedicines. The complexities and heterogenecity of both nanomedicines and cancer are further demanding the integration of highly diverse expertise to develop clinically translatable cancer nanomedicines. This progress report aims to discuss the current understanding of cancer nanomedicines between different research areas in terms of nanoparticle engineering, formulation, tumor patho-physiology and clinical medicine, as well as to identify the knowledge gaps lying at the interface between the different fields of research in nanomedicine. Here we also highlight for the necessity to harmonize the multidisciplinary effort in the research of nanomedicines in order to bridge the knowledge and to advance the full understanding in cancer nanomedicines. A paradigm shift is needed in the strategic development of disease specific nanomedicines in order to foster the successful translation into clinic of future cancer nanomedicines.Peer reviewe

Production and characterization of monoclonal anti-sphingosine-1-phosphate antibodies1

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid involved in multiple physiological processes. Importantly, dysregulated S1P levels are associated with several pathologies, including cardiovascular and inflammatory diseases and cancer. This report describes the successful production and characterization of a murine monoclonal antibody, LT1002, directed against S1P, using novel immunization and screening methods applied to bioactive lipids. We also report the successful generation of LT1009, the humanized variant of LT1002, for potential clinical use. Both LT1002 and LT1009 have high affinity and specificity for S1P and do not cross-react with structurally related lipids. Using an in vitro bioassay, LT1002 and LT1009 were effective in blocking S1P-mediated release of the pro-angiogenic and prometastatic cytokine, interleukin-8, from human ovarian carcinoma cells, showing that both antibodies can out-compete S1P receptors in binding to S1P. In vivo anti-angiogenic activity of all antibody variants was demonstrated using the murine choroidal neovascularization model. Importantly, intravenous administration of the antibodies showed a marked effect on lymphocyte trafficking. The resulting lead candidate, LT1009, has been formulated for Phase 1 clinical trials in cancer and age-related macular degeneration. The anti-S1P antibody shows promise as a novel, first-in-class therapeutic acting as a “molecular sponge” to selectively deplete S1P from blood and other compartments where pathological S1P levels have been implicated in disease progression or in disorders where immune modulation may be beneficial

TREASUREHUNT: Transients and Variability Discovered with HST in the JWST North Ecliptic Pole Time Domain Field

The JWST North Ecliptic Pole (NEP) Time Domain Field (TDF) is a $>$14 arcmindiameter field optimized for multi-wavelength time-domain science with JWST.Its location within JWST's northern continuous viewing zone offers optimalconditions for time-domain studies with JWST, ensuring year-roundobservability, absence of bright stars, and minimal Zodiacal foregroundinterference. It has been observed across the electromagnetic spectrum bothfrom the ground and from space, including with the Hubble Space Telescope(HST). As part of HST observations over 3 cycles (the "TREASUREHUNT" program),deep images were obtained with ACS/WFC in F435W and F606W that cover almost theentire JWST NEP TDF. Many of the individual pointings of these programspartially overlap, allowing an initial assessment of the potential of thisfield for time-domain science with HST and JWST. The cumulative area ofoverlapping pointings is ~88 arcmin$^2$, with time intervals between individualepochs that range between 1 day and 4$+$ years. We present the discovery of 12transients and ~100 variable sources to a depth of $m_{\rm AB} \simeq$ 29.5 mag(F606W). The majority of the transients will be supernovae, although at leasttwo are likely quasars. Most variable sources are AGN, where we find ~0.35%(0.04%) of the general $z < 6$ field galaxy population to vary at the 3$\sigma$(5$\sigma$) level. Based on a 5-year timeframe, this translates into a randomsupernova areal density of up to ~0.07 transients per arcmin$^2$ (~245deg$^{-2}$) per epoch, and a variable AGN areal density of ~1.4 variables perarcmin$^2$ (~5184 deg$^{-2}$) to these depths