Abstract
Poly-ADP-ribose polymerase (PARP) is an enzyme critical for regulating a variety of DNA damage repair mechanisms. In this study, we report that PARP inhibitor, talazoparib, showed strong ...single-agent cytotoxicity and remarkable selective activity in glioma stem-like cells (GSCs). This single agent activity was strongly correlated with EGFR amplification as shown by genomic analysis. GSCs withEGFR amplification (which occurs in about 45% of GBMs) exhibited higher oxidative base damage, DNA breaks, and genomic instability than non-amplified GSCs. To sustain the elevated basal oxidative stress, EGFR amplified GSCs harbored increased basal expression of DNA repair proteins. As a result, DNA damage and PARP-DNA complexes increased in the amplified GSCs following talazoparib treatment, which may explain the sensitivity of these GSCs to talazoparib. Further, we show that EGFR kinase activity is important for talazoparib sensitivity, as kinase-inactive EGFR mutant and EGFR knockout cell lines were resistant to talazoparib. Intriguingly, another PAPR inhibitor Olaparib, with similar PARP enzymatic inhibition potential but less PARP-trapping ability compared with talazoparib, did not show selective sensitivity in EGFR amplified GSCs. Our data provide insight into the anti-cancer activity of talazoparib through PARP inhibition and by trapping PARP-DNA complexes. In conclusion we propose the potential of EGFR amplification as a biomarker for selection of the development of personalized therapy.
Validation of multi-gene biomarkers for clinical outcomes is one of the most important issues for cancer prognosis. An important source of information for virtual validation is the high number of ...available cancer datasets. Nevertheless, assessing the prognostic performance of a gene expression signature along datasets is a difficult task for Biologists and Physicians and also time-consuming for Statisticians and Bioinformaticians. Therefore, to facilitate performance comparisons and validations of survival biomarkers for cancer outcomes, we developed SurvExpress, a cancer-wide gene expression database with clinical outcomes and a web-based tool that provides survival analysis and risk assessment of cancer datasets. The main input of SurvExpress is only the biomarker gene list. We generated a cancer database collecting more than 20,000 samples and 130 datasets with censored clinical information covering tumors over 20 tissues. We implemented a web interface to perform biomarker validation and comparisons in this database, where a multivariate survival analysis can be accomplished in about one minute. We show the utility and simplicity of SurvExpress in two biomarker applications for breast and lung cancer. Compared to other tools, SurvExpress is the largest, most versatile, and quickest free tool available. SurvExpress web can be accessed in http://bioinformatica.mty.itesm.mx/SurvExpress (a tutorial is included). The website was implemented in JSP, JavaScript, MySQL, and R.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Interplanetary (IP) shocks are perturbations observed in the solar wind. IP shocks correlate well with solar activity, being more numerous during times of high sunspot numbers. Earth‐bound ...IP shocks cause many space weather effects that are promptly observed in geospace and on the ground. Such effects can pose considerable threats to human assets in space and on the ground, including satellites in the upper atmosphere and power infrastructure. Thus, it is of great interest to the space weather community to (a) keep an accurate catalog of shocks observed near Earth, and (b) be able to forecast shock occurrence as a function of the solar cycle (SC). In this work, we use a supervised machine learning regression model to predict the number of shocks expected in SC25 using three previously published sunspot predictions for the same cycle. We predict shock counts to be around 275 ± 10, which is ∼47% higher than the shock occurrence in SC24 (187 ± 8), but still smaller than the shock occurrence in SC23 (343 ± 12). With the perspective of having more IP shocks on the horizon for SC25, we briefly discuss many opportunities in space weather research for the remainder years of SC25. The next decade or so will bring unprecedented opportunities for research and forecasting effects in the solar wind, magnetosphere, ionosphere, and on the ground. As a result, we predict SC25 will offer excellent opportunities for shock occurrences and data availability for conducting space weather research and forecasting.
Plain Language Summary Solar activity is quite correlated with sunspot numbers. Alternating periods between solar minima and minima, termed solar cycle, usually occur every ∼11 years. As a result, researchers often attempt to predict sunspot occurrences for the following solar cycle. Solar perturbations occur more frequently during periods of high solar activity, and Earth‐bound perturbations can disturb the Earth's magnetic field in geospace and on the ground, affecting satellites and power infrastructure. In this work, we use an artificial intelligence supervised model to predict the number of shock occurrences in the ongoing solar cycle (beginning December 2019) by training the model with observations of sunspots and solar perturbations in the previous two solar cycles (August 1996–December 2019). Then, sunspot number predictions for the ongoing solar cycle are applied to the model, and predictions for the solar perturbations are obtained. We find that the number of predicted solar perturbations is ∼50% higher than their occurrence number in the previous solar cycle (December 2008–December 2019). Finally, we discuss how this relatively higher number of predicted solar perturbations can impact space weather research given the unprecedented number of data sets available in geospace and on the ground in the upcoming years.
Key Points SSN and shock count data in SC23‐24 are used with SSN predictions for SC25 in a supervised regression model to estimate shock counts in SC25 We predict SC25 (275) will have ∼48% more shocks in comparison to SC24 (187), but it will have fewer shocks in comparison to SC23 (343) SC25 will offer unprecedented opportunities for space weather research given the availability of many data sets from space to the ground
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