tbuckley/cabot-search huggingface dataset:
Image-level detection of arterial occlusions in 4D-CTA of acute stroke patients using deep learning
Authors: Midas Meijs, Frederick J.A. Meijer, Mathias Prokop, Bram van Ginneken, Rashindra Manniesing
Journal: Medical Image Analysis (2020)

The triage of acute stroke patients is increasingly dependent on four-dimensional CTA (4D-CTA) imaging. In this work, we present a convolutional neural network (CNN) for image-level detection of intracranial anterior circulation artery occlusions in 4D-CTA. The method uses a normalized 3D time-to-signal (TTS) representation of the input image, which is sensitive to differences in the global arrival times caused by the potential presence of vascular pathologies. The TTS map presents the time within the cranial cavity at which the signal reaches a percentage of the maximum signal intensity, corrected for the baseline intensity. The method was trained and validated on (n=214) patient images and tested on an independent set of (n=279) patient images. This test set included all consecutive suspected-stroke patients admitted to our hospital in 2018. The accuracy, sensitivity, and specificity were 92%, 95%, and 92%. The area under the receiver operating characteristics curve was 0.98 (95% CI: 0.95- 0.99). These results show the feasibility of automated stroke triage in 4D-CTA.
Abstract 6077: The role of STAT3 and Snai2 in ovarian cancer metastasis
Authors: David F. Walker, Sarah J. Lacroix, Yuri Makar, Sarah R. Walker
Journal: Cancer Research (2020)

Abstract Ovarian cancer remains a deadly disease due in part to ovarian cancer metastasis. Recent work has demonstrated that ovarian cancer forms clusters of cells (spheroids) that attach to the peritoneum by clearing the mesothelial cell layer and then invade the underlying matrix to metastasize. Understanding the key pathways and downstream transcription factors that are driving ovarian cancer metastasis may allow us to develop new therapies to treat metastatic ovarian cancer. Importantly, we have found that the STAT3 transcription factor is necessary for mesothelial clearance by ovarian spheroids. To identify key downstream STAT3 target genes involved in ovarian cancer metastasis, we analyzed publicly available STAT3 chromatin immunoprecipitation (ChIP)-seq datasets for genes associated with epithelial-to-mesenchymal transition. One of the genes that we identified was the transcriptional modulator Snai2 (Slug). To verify that Snai2 was downstream of STAT3, we transfected ovarian cancer cells with siRNA to STAT3 and analyzed Snai2 gene expression. We found reduced expression of Snai2 with siRNA to STAT3 suggesting that STAT3 upregulates Snai2 expression. To determine the effects of Snai2 on mesothelial clearance by ovarian spheroids, we transfected ovarian cancer cells with siRNA to Snai2 or control, generated spheroids, and performed a mesothelial clearance assay. We found that reduced expression of Snai2 decreased the ability of the ovarian cancer cells to clear the mesothelial cell layer suggesting that Snai2 plays an important role in the early stages of ovarian cancer metastasis. Recognizing that Snai2 is a transcriptional modulator, we were interested in determining if Snai2 affected STAT3 activity. Analysis of available Snai2 ChIP-seq data identified three putative Snai2 binding sites associated with the STAT3 gene, suggesting that Snai2 may also regulate STAT3 gene expression. To determine if Snai2 affects STAT3 gene expression, ovarian cancer cells were transfected with siRNA to Snai2 and STAT3 mRNA expression was analyzed. From this, we found that reducing Snai2 expression also reduced STAT3 expression. Taken together, our data suggests that STAT3 and Snai2 form a feedforward loop promoting upregulation of each other and together they promote the early stages of ovarian cancer metastasis. Therefore, developing an inhibitor to one of these transcription factors would affect both proteins and may be beneficial to prevent or treat metastatic ovarian cancer. Citation Format: David F. Walker, Sarah J. Lacroix, Yuri Makar, Sarah R. Walker. The role of STAT3 and Snai2 in ovarian cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6077.
Abstract 4879: Identification of degron motifs and mutations by analyzing a deep neural network
Authors: Cynthia Chen, Collin Tokheim, Shirley Liu
Journal: Cancer Research (2020)

Abstract Degrons, short amino acid sequences on protein substrates, play a critical role in the ubiquitin-proteasome system (UPS), which regulates over 80 percent of protein degradation in cells. When recognized by E3 ubiquitin ligases, degrons signal the destruction of its substrate protein, determining the regulatory specificity of the UPS. While a few degrons have been reported to be affected by mutations driving cancer growth, the effect of specific mutations on degrons remains largely unidentified. In this study, we analyze a deep neural network model that predicts the likelihood of an input protein sequence to contain a degron. To characterize the important C-terminal degron motifs learned by the model, we ran computational methods including sequence ranking and selection, enrichment analyses, and sequence logo visualization. This revealed the discovery of 101 significant degron motifs across lengths 2, 3, and 4. While previous studies suggested that di-amino acid motifs might be the primary source of c-end degron, the new motifs suggest that additional complexity might exist with a longer extended degron. Using these putative motifs as targets for mutations, we performed in silico mutagenesis to identify high-impact amino acid mutations that cause degron loss or gain. Our discovery of degron motif-mutation pairs could inform the development of targeted small-molecule drugs for cancer treatments and identification mutational biomarkers used for early detection of cancers. Citation Format: Cynthia Chen, Collin Tokheim, Shirley Liu. Identification of degron motifs and mutations by analyzing a deep neural network [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4879.
Abstract 5039: SCD1/FADS2 and ferroptosis signalings orchestrate ovarian cancer cell metabolism and metastatic progression in peritoneal metastases
Authors: Yang Xuan, Mingo MH Yung, Arvin FS Chen, Hextan YS Ngan, David W Chan
Journal: Cancer Research (2020)

Abstract Peritoneal metastases are common and usually associated with poor prognosis in advanced ovarian cancers. Emerging evidence indicates that the ascites microenvironment provides a key reservoir of growth factors and free fatty acids for promoting metastatic recurrence and chemoresistance of ovarian cancers. However, how the metastatic ovarian cancer cells adapt and utilize such a unique tumor microenvironment remains elusive. Here, we report that ovarian cancer cells co-cultured in ascites or omental conditioned medium (OCM) enhance their oncogenic capacities through elevated lipid metabolism. RNA sequencing (RNA-seq) and lipidomic profiling analyses revealed two key mediators of UFAs, Stearoyl-CoA Desaturase-1 (SCD1) and Fatty acid Desaturase-2 (FADS2) were upregulated accompanied with the accumulation of poly- and mono-unsaturated fatty acids (UFAs) in ovarian cancer cells co-cultured in OCM. Enforced expression of either SCD1 or FADS2 promotes cancer stemness, in vitro and ex vivo tumor colony formation, and cell migration/invasion through activation of NFκB signaling. SCD1/FADS2 increases not only UFAs accumulation but also the cell membrane fluidity which is crucial for the epithelial-mesenchymal transition (EMT) and metastatic potentials. On the other hand, RNA-Seq analysis on SCD1/FADS2-depleted ovarian cancer cells showed the ferroptotic activities were inversely correlated with SCD1/FADS2. Of note, either knockout of SCD1/FADS2 or co-treatment of Erastin could enhance cisplatin-induced cytotoxicity through the elevation of iron-mediated reactive oxygen species (ROS), and subsequently led ferroptosis by upregulation of GPX4/xCT expressions in ovarian cancer cells. Higher tumorigenic capacity expressed in iron-rich ovarian cancer cells, which contains sphere formation, EMT potential and cell viability. Taken together, SCD1/FADS2 and ferroptosis signaling pathways orchestrate the metabolic activities, ROS stresses and cellular iron homeostasis during the metastatic progression of ovarian cancer cells in peritoneum microenvironment. Hence, targeting these signaling cascades by the drug cocktail/combination strategy could reduce the risk of metastatic recurrence and chemoresistance in advanced ovarian cancers. Citation Format: Yang Xuan, Mingo MH Yung, Arvin FS Chen, Hextan YS Ngan, David W Chan. SCD1/FADS2 and ferroptosis signalings orchestrate ovarian cancer cell metabolism and metastatic progression in peritoneal metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5039.
“I Think It’s Been Met With a Shrug:” Oncologists’ Views Toward and Experiences With Right-to-Try
Authors: Cambray Smith, Jeremiah Stout, Alex A Adjei, Jan Buckner, Mark Wentworth, Jon Tilburt, Zubin Master
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background The federal Right-to-Try (RTT) Act created an alternate regulatory pathway for preapproval access to investigational drugs. A few studies have examined the experiences of physicians with the Food and Drug Administration’s Expanded Access Programs, but to our knowledge, no study has yet to examine their attitudes and experiences toward RTT. Methods This study explored the views of 21 oncologists at a major cancer center with 3 main sites across the United States using semi-structured interviews and qualitative analysis. Participants were selected to have experience with Expanded Access Programs. Results Most oncologists had limited familiarity with RTT, and several reported confusion about the legislation, including whether patients have a right to investigational drugs and an obligation for companies to provide them. Although oncologists were interested in decreased regulatory burdens, 3 areas of concern were articulated: lack of safety and oversight, unclear structure and no provision for data collection, and potential heightening of patient expectations. Only 4 oncologists had experience discussing RTT, and none formally attempted to obtain the drug through this mechanism. Participants questioned the practicality of RTT legislation and suggested alternative ways to improve access. Conclusions The study provides foundational empirical data underlying challenging ambiguities by experienced oncologists familiar with off-trial use of investigational therapeutics and reaffirms the role of physicians and regulatory bodies in mitigating the risks of investigational drugs. Our findings highlight the need for medical centers to inform oncologists about RTT and other preapproval pathways so that they are able to address questions from patients interested in nontrial investigational drugs.
Abstract 3270: Dual blockade of PD-L1 and LAG-3 using a bispecific antibody improves anti-tumor immunity
Authors: Haiqing Ni, Yajing Qiu, Hua Jing, Pan Zhang, Bingliang Chen, Zhihai Wu, Shuaixiang Zhou, Michael Yu, Junjian Liu
Journal: Cancer Research (2020)

Abstract Background: Anti-PD-1/PD-L1 treatments are effective in a fraction of patients with advanced malignancies. However, the majority of patients still do not respond. Resistance to cancer immunotherapy can be mediated by additional immune checkpoints. Lymphocyte-activation gene 3 (LAG-3) is a member of the Ig superfamily and participates in immune suppression. Combination of anti-PD-1 and anti-LAG-3 showed synergistic anti-tumor effect in preclinical mouse models and early clinical trials. Here, we develop IBI323, an anti-PD-L1/LAG-3 bispecific antibody, which preserves the dual pathway blockade function while processes new biological functions. Material &amp; Methods: The binding affinity of IBI323 to antigens were measured by Fortebio and confirmed at cellular level using PD-L1 overexpressing cells and primary T cell. IBI323 was also assessed by ELISA for PD-1 and LAG-3 pathway blocking function. IBI323 mediated PD-L1+ and LAG-3+ cells bridging was evaluated by flow cytometry. Anti-tumor activity of IBI323 was evaluated in human PD-L1 knock-in mice bearing PD-L1 overexpressing MC38 tumors. Besides tumor growth, the frequencies and quality of the tumor-specific T cells were assessed by flow cytometry. In addition, florescence labeled antibodies was used for detecting the biodistribution of IBI323 in vivo. Results: IBI323 bound to PD-L1 and LAG-3 with high affinity (KD &amp;lt;1 nm). At cellular level, IBI323 bound to PD-L1 overexpressing cells and LAG-3+ T cells in a similar manner to parental antibodies. IBI323 was able to block PD-1/PD-L1 and LAG3/MHCII interactions simultaneously. Moreover, bridging between PD-L1+ cells and LAG-3+ cells was observed in the presence of IBI323 in vitro. Correspondingly, IBI323 was mainly distributed at the location of PD-L1+ tumor in vivo. In mice harboring established PD-L1+ MC38 tumor, IBI323 treatment was superior to combination of individual anti-PD-L1 and LAG-3 antibodies. The better activity of IBI323 treatment was reflected by an enhanced number of tumor-specific CD8+ cytotoxic T cells. Conclusions: We developed a novel bispecific antibody against PD-L1 and LAG-3, which resulted in dramatic tumor growth inhibition. The anti-tumor efficacy of IBI323 was better than either monotherapy or anti-PD-L1 and LAG-3 combination treatment. Based on the encouraging preclinical results, IBI323 could soon be evaluated in clinical trials. Citation Format: Haiqing Ni, Yajing Qiu, Hua Jing, Pan Zhang, Bingliang Chen, Zhihai Wu, Shuaixiang Zhou, Michael Yu, Junjian Liu. Dual blockade of PD-L1 and LAG-3 using a bispecific antibody improves anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3270.
Abstract 3110: In depth comparison of cell free DNA blood collection tubes
Authors: Joel Desharnais, Jacob M. Vasquez, Katya J. Reshatoff, Quyen Bui, Han-Mei Chen, Billyana Tsvetanova, Jerry Lu, Amber N. Murray, Gina L. Costa
Journal: Cancer Research (2020)

Abstract Liquid biopsy continues to gain traction as a minimally invasive method to monitor biomarkers associated with malignancy and metastasis such as cell-free DNA (cfDNA). However, cell-free DNAs are present in low quantities and are prone to rapid degradation and contamination, which presents challenges for the detection of rare cfDNA targets. Higher molecular weight genomic DNA from poorly stabilized leukocytes can also serve to contaminate plasma, compromising liquid biopsy assay results by increasing the total amount of extracted DNA while diluting rare cfDNA targets; leading to sample rejection or false negative results. Efficient and robust preservation of cfDNA and prevention of leukocyte lysis is thus essential for the accuracy of downstream tests, and several blood collection tubes (BCTs) designed to stabilize cfDNA are now commercially available. The work presented here evaluates LBgard® Blood Tubes (Biomatrica), the Streck Cell-Free DNA BCTs® (Streck), and PAXgene Blood ccfDNA Tubes (PreAnalytix) for analysis of cfDNA. Healthy donor blood was collected into collection tubes, and the samples were either stored for several days at a range of temperatures or subjected to various shipping conditions. Several metrics were evaluated, including hemolysis, plasma recovery, cfDNA preservation, contamination with genomic DNA (gDNA), and quantitation of cfDNA targets. Differences were observed between the various tubes evaluated, especially when tested under real-world stress shipping conditions. Data reports performance metrics and evaluations across the multiple formulations of BCTs and highlights the criticality of collection tube selection in biomarker investigation and study. Citation Format: Joel Desharnais, Jacob M. Vasquez, Katya J. Reshatoff, Quyen Bui, Han-Mei Chen, Billyana Tsvetanova, Jerry Lu, Amber N. Murray, Gina L. Costa. In depth comparison of cell free DNA blood collection tubes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3110.
Abstract 5339: Paradoxical androgen receptor regulation by small molecule enantiomers
Authors: Katherin Patsch, Chao Liu, Boris Kashemirov, Harish Sura, Grzegorz Zapotoczny, Yuanye Sun, Pavan P. Shah, Jonathan E. Katz, Sujatha Chilakala, Ah Young Joo, Nolan Ung, Maya Aljehani, Ren X. Sun, David B. Agus, Daniel Ruderman, Charles E. McKenna
Journal: Cancer Research (2020)

Abstract Small molecules that target the androgen receptor (AR) are the mainstay of therapy for lethal castration-resistant prostate cancer (CRPC), but they ultimately lead to resistance and progression to terminal disease. While individual resistance-associated AR mutations have been identified, the underlying mechanisms remain poorly understood. Here, we report a new class of AR-targeting compounds derived from the anti-androgen BMS-641988 (N-((3aR,4R,5R,7R,7aS)-2-(4-cyano-3-(trifluoromethyl)phenyl)-4,7-dimethyl-1,3-dioxooctahydro-1H-4,7-epoxyisoindol-5-yl)ethanesulfonamide) that reveal unexpected biological behavior: as expected, the C-5 (R)-enantiomers are antagonists, however the corresponding (S)-enantiomers, including the previously unknown C-5 (S)-enantiomer of BMS-641988 itself, are potent agonists of AR, with ED50 values comparable to dihydrotestosterone and R1881. A series of in vitro assays that interrogate different steps of AR functionality–including AR binding via fluorescence polarization, nuclear translocation and hyperspeckling via live cell confocal microscopy, ARE-luciferase, and RT qPCR arrays–confirm that the (R)-enantiomers are potent antagonists of AR in multiple cell lines, including AR T877A mutation-expressing LNCaP and AR overexpressing VCaP. While these cells are virtually resistant to BMS-641988, two of the novel derivatives, (R)-USC-1702 and (R)-USC-1707, inhibited their growth with IC50 values in the lower nM range. Importantly, these compounds do not produce the toxic metabolite that led to the clinical failure of BMS-641988. This is the first documented evidence of small molecule enantiomer pairs showing opposite functional effects while targeting AR. This new AR regulation duality augments our understanding of AR function and may have implications for anti-androgen drug development. Citation Format: Katherin Patsch, Chao Liu, Boris Kashemirov, Harish Sura, Grzegorz Zapotoczny, Yuanye Sun, Pavan P. Shah, Jonathan E. Katz, Sujatha Chilakala, Ah Young Joo, Nolan Ung, Maya Aljehani, Ren X. Sun, David B. Agus, Daniel Ruderman, Charles E. McKenna. Paradoxical androgen receptor regulation by small molecule enantiomers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5339.
Abstract 3710: Combinatorial micro RNA therapy can be used as potential cell cycle inhibitors to treat lung cancer
Authors: A K M Nawshad Hossian
Journal: Cancer Research (2020)

Abstract Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Among the 18.1 million of total cancer patients last year, 2.1 million of the new cases were of LC worldwide. The poor prognosis, higher incidence, and mortality rate make this disease a devastating type of cancer. Cell cycle inhibition is one of the prominent choices among researchers in cancer treatment. Different cell cycle inhibitors are developed by scientists where the cyclin-dependent kinase (CDK) inhibitors are among the most frequently researched. Just recently, 3 CDK inhibitors received FDA-approval for treatment of specific breast cancer subtypes, but no CDK inhibitors currently exist for LC patient treatment. Thus, there is a need for molecules that regulate cell cycle progression and CDK expression. Micro RNAs (miRNAs) are gene-expression regulatory molecules. Among several miRs, we selected miR-143 and miR-506 to regulate CDK1 and CDK4/6, respectively. qPCR and RNA-sequencing indicated that this combinatorial miR therapy caused downregulation of the respective CDK1, 4, and 6 genes in H358 and H1975 lung cancer cell lines. This RNA inhibition corresponded to protein levels downregulation, as detected by western blot analysis. Further investigation found that this treatment caused significant halt of the cell cycle progression, which is markedly stronger than the commercially available CDK inhibitors, Ribociclib and Flavopiridol. We also identified the combined miR-143 and miR-506 caused significant increase of the apoptotic cell population at both 24 and 48 h post-treatment, as detected by an Annexin V/PI analysis. Interestingly, low or no apoptotic impact was observed in HFL1 normal lung fibroblast cells by the combinatorial miR treatment, indicating a cancer-cell specific activity. Upstream pathway analysis through RNA-sequencing using Ingenuity Pathway Analysis software (IPA; Qiagen) indicated a potential ERK-mediation on the activity of the combinatorial miR treatment. Our analysis of the ERK pathway using MAPK (ERK) inhibitors indicated an ERK-independent cell cycle inhibitory activity of the two miRs. Through further analysis of the RNA-Seq data, we observed a potential inhibition of the cellular migration and invasion activity of the cells, which was confirmed by a cell migration assay. In summary, combinatorial treatment of miR-143 and miR-506 has a significant impact on the cell cycle, overall survival, and migration of LC cells, which still merits further study. Citation Format: A K M Nawshad Hossian. Combinatorial micro RNA therapy can be used as potential cell cycle inhibitors to treat lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3710.