Dynamic changes in gene expression in vivo predict prognosis of tamoxifen-treated patients with breast cancer

Introduction: Tamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor (ER)-positive breast cancer. However, there is still a need for biomarkers that reliably predict endocrine sensitivity in breast cancers and these may well be expressed in a dynamic manner. Methods: In this study we assessed gene expression changes at multiple time points (days 1, 2, 4, 7, 14) after tamoxifen treatment in the ER-positive ZR-75-1 xenograft model that displays significant changes in apoptosis, proliferation and angiogenesis within 2 days of therapy. Results: Hierarchical clustering identified six time-related gene expression patterns, which separated into three groups: two with early/transient responses, two with continuous/late responses and two with variable response patterns. The early/transient response represented reductions in many genes that are involved in cell cycle and proliferation (e.g. BUB1B, CCNA2, CDKN3, MKI67, UBE2C), whereas the continuous/late changed genes represented the more classical estrogen response genes (e.g. TFF1, TFF3, IGFBP5). Genes and the proteins they encode were confirmed to have similar temporal patterns of expression in vitro and in vivo and correlated with reduction in tumour volume in primary breast cancer. The profiles of genes that were most differentially expressed on days 2, 4 and 7 following treatment were able to predict prognosis, whereas those most changed on days 1 and 14 were not, in four tamoxifen treated datasets representing a total of 404 patients. Conclusions: Both early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner. Temporal expression of therapy-response genes is clearly an important factor in characterising the response to endocrine therapy in breast tumours which has significant implications for the timing of biopsies in neoadjuvant biomarker studies.Publisher PDFPeer reviewe

The NANOGrav 15-year Data Set: Observations and Timing of 68 Millisecond Pulsars

We present observations and timing analyses of 68 millisecond pulsars (MSPs) comprising the 15-year data set of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav). NANOGrav is a pulsar timing array (PTA) experiment that is sensitive to low-frequency gravitational waves. This is NANOGrav's fifth public data release, including both "narrowband" and "wideband" time-of-arrival (TOA) measurements and corresponding pulsar timing models. We have added 21 MSPs and extended our timing baselines by three years, now spanning nearly 16 years for some of our sources. The data were collected using the Arecibo Observatory, the Green Bank Telescope, and the Very Large Array between frequencies of 327 MHz and 3 GHz, with most sources observed approximately monthly. A number of notable methodological and procedural changes were made compared to our previous data sets. These improve the overall quality of the TOA data set and are part of the transition to new pulsar timing and PTA analysis software packages. For the first time, our data products are accompanied by a full suite of software to reproduce data reduction, analysis, and results. Our timing models include a variety of newly detected astrometric and binary pulsar parameters, including several significant improvements to pulsar mass constraints. We find that the time series of 23 pulsars contain detectable levels of red noise, 10 of which are new measurements. In this data set, we find evidence for a stochastic gravitational-wave background.Comment: 90 pages, 74 figures, 6 tables; published in Astrophysical Journal Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave Background. For questions or comments, please email [email protected]

Scientific opportunies for bERLinPro 2020+, report with ideas and conclusions from bERLinProCamp 2019

The Energy Recovery Linac (ERL) paradigm offers the promise to generate intense electron beams of superior quality with extremely small six-dimensional phase space for many applications in the physical sciences, materials science, chemistry, health, information technology and security. Helmholtz-Zentrum Berlin started in 2010 an intensive R\&D programme to address the challenges related to the ERL as driver for future light sources by setting up the bERLinPro (Berlin ERL Project) ERL with 50 MeV beam energy and high average current. The project is close to reach its major milestone in 2020, acceleration and recovery of a high brightness electron beam. The goal of bERLinProCamp 2019 was to discuss scientific opportunities for bERLinPro 2020+. bERLinProCamp 2019 was held on Tue, 17.09.2019 at Helmholtz-Zentrum Berlin, Berlin, Germany. This paper summarizes the main themes and output of the workshop

Undulator Photon Beams with Orbital Angular Momentum

Photons carrying an orbital angular momentum OAM are present in the off axis radiation of higher harmonics of helical undulators. Usually, the purity and visibility of OAM carrying photons is blurred by the electron beam emittance. However, high brightness OAM beams are expected in Ultimate Storage Rings USRs and FELs, and they may trigger a new class of experiments utilizing the variability of the topological charge, a 3rd degree of freedom besides the wavelength and the polarization. In 2013 a 99eV OAM beam from a helical undulator has been observed for the first time at the storage ring BESSY II. We discuss the sensitivity of the conducted interference experiment on the emittance and the settings of the two undulators which were involved. Furthermore, we propose another interference experiment which will be very robust against the undulators field settin

Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond

The advent of mitogen-activated protein kinase (MAPK) inhibitors that directly inhibit tumor growth and of immune checkpoint inhibitors (ICI) that boost effector T cell responses have strongly improved the treatment of metastatic melanoma. In about half of all melanoma patients, tumor growth is driven by gain-of-function mutations of BRAF (v-rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation. Patients with a BRAF mutation are regularly treated with a combination of BRAF and MEK (MAPK/ERK kinase) inhibitors. Next to the antiproliferative effects of BRAF/MEKi, accumulating preclinical evidence suggests that BRAF/MEKi exert immunomodulatory functions such as paradoxical ERK activation as well as additional effects in non-tumor cells. In this review, we present the current knowledge on the immunomodulatory functions of BRAF/MEKi as well as the non-intended effects of ICI and discuss the potential synergistic effects of ICI and MAPK inhibitors in melanoma treatment