<div>AbstractPurpose:<p>To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2′-deoxyguanosine (THIO) in gliomas both <i>in vitro</i> and <i>in vivo</i>.</p>Experimental Design:<p>A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO.</p>Results:<p>THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model.</p>Conclusions:<p>The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.</p></div>
Abstract Both genomic and transcriptomic signatures have been developed to predict responses of metastatic melanoma to immune checkpoint blockade (ICB) therapies; however, most of these signatures are derived from pre-treatment biopsy samples. Here, we build pathway-based super signatures in pre-treatment (PASS-PRE) and on-treatment (PASS-ON) tumor specimens based on transcriptomic data and clinical information from a large dataset of metastatic melanoma treated with anti-PD1-based therapies as the training set. Both PASS-PRE and PASS-ON signatures are validated in three independent datasets of metastatic melanoma as the validation set, achieving area under the curve (AUC) values of 0.45–0.69 and 0.85–0.89, respectively. We also combine all test samples and obtain AUCs of 0.65 and 0.88 for PASS-PRE and PASS-ON signatures, respectively. When compared with existing signatures, the PASS-ON signature demonstrates more robust and superior predictive performance across all four datasets. Overall, we provide a framework for building pathway-based signatures that is highly and accurately predictive of response to anti-PD1 therapies based on on-treatment tumor specimens. This work would provide a rationale for applying pathway-based signatures derived from on-treatment tumor samples to predict patients’ therapeutic response to ICB therapies.
With the growth of the digital advertising market, it has become more important than ever to target the desired audiences. Among various demographic traits, gender information plays a key role in precisely targeting the potential consumers in online advertising and ecommerce. However, such personal information is generally unavailable to digital media sellers. In this paper, we propose a novel task-specific multi-task learning algorithm to predict users' gender information from their video viewing behaviors. To detect as many desired users as possible, while controlling the Type I error rate at a user-specified level, we further propose Bayes testing and decision procedures to efficiently identify male and female users, respectively. Comprehensive experiments have justified the effectiveness and reliability of our framework.
<p>Supplementary Figure 5. (A-C) The heatmap of proteins changed by THIO in M059K, LN229 and U87MG cells from RPPA data. (D-F) Western blot was performed to confirm the change of these proteins in H4 (more sensitive to THIO) (D), U87MG (less sensitive to THIO) (E), and U251MG (more resistant to THIO) (F) after treatment with THIO at 5 µM. Actin serves as a loading control. (G) Heatmap of pathways regulated by THIO in M059K, LN229 and U87MG cells.</p>
<p>Supplementary Figure 1. (A-B) Successful labeling of CellTrace Violet for M059K and H4 cells. M059K and H4 cells were labeled with a cell membrane dye CellTrace Violet and verified the success of labeling by FACS. (C-D) Cell viability of M059K and H4 following THIO treatment. M059K and H4 cells were treated with control medium or THIO at 5µM and then determined the cell viability percentage via detecting PSVue643 and PI by FACS. (E-F) Western blot results of time-course and dose-titration experiments in M059K and H4. For the time-course experiment, cells were treated with THIO at 5µM and proteins were tested at 0, 24, 48 and 72 hours. For dose-titration experiments, cells were treated with serious doses of THIO for 72 hours. TMZ functions as control. Actin serves as a loading control.</p>
<p>Supplementary Figure 6. (A) Creation of primary patient-derived glioblastoma organoids. (B) Quantification of tumor weight of U87MG xenograft model. (C) The curve of body weight of mice of U87MG xenograft model during THIO treatment. (D) Quantification of tumor weight of GBM PDX model. (E) The curve of body weight of mice of GBM PDX model during THIO treatment. (F) The curve of body weight of mice of U251MG xenograft model during THIO treatment.</p>
<p>Supplementary Figure 6. (A) Creation of primary patient-derived glioblastoma organoids. (B) Quantification of tumor weight of U87MG xenograft model. (C) The curve of body weight of mice of U87MG xenograft model during THIO treatment. (D) Quantification of tumor weight of GBM PDX model. (E) The curve of body weight of mice of GBM PDX model during THIO treatment. (F) The curve of body weight of mice of U251MG xenograft model during THIO treatment.</p>
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