tbuckley/cabot-search huggingface dataset:
Abstract 4254: Quality assessment platform for molecular pathology from non small cell lung cancer histopathology images using deep learning: A nationwide study of central laboratory in South Korea
Authors: Tae-Jung Kim, Ho Chul Kang, Yonggeun Lee, Seokman Seo, Donghwan Kim
Journal: Cancer Research (2020)

Abstract Molecular testing became the most important part of lung cancer diagnostics. Integration of various molecular testing such as real-time PCR, fluorescent in situ hybridization (FISH) and next-generation sequencing into routine clinical practice and their systemic quality control is challenging to a pathologist and even more in the central laboratory. In this study, we trained a variant of DenseNet, a convolutional neural network model with the highest performance in image classification and suitable for quality assessment. Train dataset is composed of the arbitrarily classified dataset made and assessed by a professional pathologist during routine molecular test using whole-slide tissue images and molecular profiles including DNA density and the signal intensity of FISH obtained from 15,000 tests from lung cancer biopsies and resections, which were sent to the central laboratory for molecular studies from 45 hospitals nationwide. The performance of our platform is tested and compared to the quality assessment dataset made from each a general pathologist and a technician. The performance of our method for classifying DNA concentration and the signal intensity of FISH is comparable to that of a general pathologist and we are under improving its average area under the curve (AUC) over 0.95. This result suggests that deep learning model based on a convolutional neural network can assist pathologists for rigorous assessing quality of tissue morphology and signal of FISH for tissue samples with various molecular quality before or during the molecular test and, furthermore, can be applied to quality control of lung cancer molecular testing in a central laboratory. Citation Format: Tae-Jung Kim, Ho Chul Kang, Yonggeun Lee, Seokman Seo, Donghwan Kim. Quality assessment platform for molecular pathology from non small cell lung cancer histopathology images using deep learning: A nationwide study of central laboratory in South Korea [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 4254.
Abstract LB-031: The significant role of 14-3-3 sigma including signal transduction, cell cycle regulation, and malignant transformation in human gastric cancer
Authors: Jiyoon Jung, Kyunghee Lee, sungae Koh, sangwoon Kim
Journal: Cancer Research (2020)

Abstract Background: 14-3-3 protein family have many diverse functions in cellular responses including cell cycle regulation, apoptosis and malignant transformation in a broad range of organisms. 14-3-3 sigma induces G2 arrest enabling the repair of damaged DNA. Especially 14-3-3 sigma is frequently lost in tumor cells and surrounding tissues, indicate that becomes lost at an early stage in invasive cancer. The purpose of this study is to identify the role of HGF upregulated 14-3-3 sigma associated with cancer cell proliferation and invasion in gastric cancer and to identify the role of 14-3-3 sigma level in vivo by analysis 14-3-3 serum level in gastric cancer patients who underwent gastrectomy. Methods: In our study we used cell culture, Northern blotting, cDNA microarray analysis, western blotting, RT-PCR, Zymography, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 14-3-3 sigma knock-down with short hairpin RNA (shRNA), electrophoresis mobility-shift assay, chromatin immunoprecipitation assay, Standard two chamber invasion assay. And we conducted the 14-3-3 sigma ELISA (enzyme-linked immunosorbent assay) of 37 blood samples of patients, who underwent gastrectomy for gastric cancer. Results: First, we confirmed that the expression level of 14-3-3 sigma was up-regulated by HGF(hepatocyte growth factor) in gastric cancer cell. To identify associated pathway of HGF-induced 14-3-3 sigma about MMP-1 (matrix metalloproteinase-1) expression, the cells were treated with MEK (Mitogen-activated protein kinase kinase) inhibitor(PD098059) and then analyzed by Western blotting. The HGF-mediated MMP-1 protein level was decreased with PD098059. The role for 14-3-3 sigma associated with MMP-1 was determined by knock down cell of 14-3-3 sigma. 14-3-3 sigma-sh RNA cells showed a decreased level of MMP-1, pERK and pp38. HGF-mediated cell proliferation and in vitro invasion was decreased in 14-3-3 sigma knock down cell. We also identified that 14-3-3 sigma serum level was statistically significant decreased after gastrectomy in gastric cancer patients with stage 2 or 3. (p value &amp;lt; 0.05) Conclusions: Our results support the hypothesis that 14-3-3 sigma plays an important role in the cell proliferation in gastric cancer, and knock down this domain, it can be preventing to gastric cancer progression. And 14-3-3 sigma serum level is associated with status of treatment locally advanced gastric cancer. Citation Format: Jiyoon Jung, Kyunghee Lee, sungae Koh, sangwoon Kim. The significant role of 14-3-3 sigma including signal transduction, cell cycle regulation, and malignant transformation in human gastric 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 LB-031.
Abstract 2130: Human papillomavirus and hepatitis B virus in situ tumor oncoviral genotype and coinfection drive oncogenesis and patient clinical response in cross cancer analysis
Authors: Adrian P. Bubie, Barbara Testoni, Fabien Zoulim, Brett Miles, Marshall Posner, Augusto Villanueva, Bojan Losic
Journal: Cancer Research (2020)

Abstract Genotype of hepatitis B virus (HBV) and human papillomavirus (HPV) infection is well known as a significant risk factor in developing liver (HCC), cervical, and head and neck cancers. However, the effect of tumor viral genotype and single-virus coinfection in driving oncogenesis and striating patient survival is generally unclear, as previous studies have not exhaustively genotyped viral-cofactors or profiled viral gene expression in tumors. In this work, we develop and deploy a new scalable, high throughput dynamic sequence alignment tool that facilitates extremely sensitive and precise oncoviral genotype deconvolution using tumor RNA sequencing data from 536 virally infected liver, cervical, and head and neck tumors across several cohorts. Pairing these results with tumor gene expression and survival analyses, we find HBV genotype C (HBV-C) associated HCC patients (n=79) are significantly upregulated in cancer proliferation and decreased cancer survival (FDR&amp;lt;0.01) compared to HBV genotype B associated tumors (n=23). Across 3 liver cancer cohorts, oncogenes TERT, MLL4, and FN1 are found recurrently integrated in HBV-C but not HBV-B. HPV clade a9 infected cervical cancers (n=173) are associated with more aggressive tumor growth and worse survival than HPV clade a7 (n=39) infected tumors (FDR&amp;lt;0.01), and are enriched in COSMIC mutational signatures linked with defective DNA repair and hypermutation. Furthermore, we demonstrate that HPV coinfection may drive patient response as neoantigens from cervical tumors with multiple HPV infections (n=18) are more immunogenic on average than single-infection tumors (n=23), controlling for HPV genotype (p&amp;lt;0.001). Finally, we compare HPV gene expression in cervical and head and neck patients, demonstrating that HPV genotype drives viral gene expression over cancer type (p&amp;lt;0.0001), and indicating viral protein expression may be similar across episomal and integration-based infections. Our results illustrate that HBV and HPV genotype, and coinfection of tumor with multiple genotypes, serve as significant predictors of patient survival and tumor immune responsiveness, and should be considered alongside clinical covariates to improve survival and treatment models. Citation Format: Adrian P. Bubie, Barbara Testoni, Fabien Zoulim, Brett Miles, Marshall Posner, Augusto Villanueva, Bojan Losic. Human papillomavirus and hepatitis B virus in situ tumor oncoviral genotype and coinfection drive oncogenesis and patient clinical response in cross cancer analysis [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 2130.
Abstract 3840: KLF5 acetylation promotes bone metastatic growth of prostate cancer by activating CXCR4/IL-11 and subsequent osteoclast differentiation
Authors: Baotong Zhang, Yixiang Li, Qiao Wu, Lin Xie, Benjamin Barwick, Jin-Tang Dong
Journal: Cancer Research (2020)

Abstract Advanced prostate cancer most commonly spreads to bones. Although denosumab or zoledronic acid is recommended for prostate cancer patients with bone metastases to prevent or delay skeletal-related events, no significant benefits in terms of cancer-specific and overall survival have been observed. Some chemotherapies are available for the treatment of bone metastasis, but eventually all such tumors develop resistance. Additionally, the underlying mechanisms of prostate cancer bone metastasis and its resistance to chemotherapy are still poorly understood. In this study, we report that TGF-β-induced acetylation of the basic transcription factor Krüppel-like factor 5 (KLF5) frequently occurred in prostate cancer cells located in both the mouse and human bone microenvironments. Using multiple in vitro and in vivo systems, we demonstrated that tumor cells expressing acetylated KLF5 (Ac-KLF5) enhanced prostate cancer-induced bone lesions by promoting osteoclast differentiation. As revealed by RNA-Seq and ChIP-Seq analyses, Ac-KLF5 transcriptionally activated CXCR4 expression, the silence of which attenuated Ac-KLF5-enhanced osteoclast differentiation. A further screening on the paracrine signaling indicates that IL-11 mediated the promoting effect of the Ac-KLF5/CXCR4 axis on osteoclast differentiation. These findings indicate that the TGF-β/Ac-KLF5/CXCR4/IL-11 signaling axis from bone to tumor and then to bone again is a crucial pathway responsible for TGF-β mediated vicious cycle in bone metastasis. More importantly, targeting CXCR4 using FDA approved drugs AMD3100 selectively sensitizes Ac-KLF5-expressing tumors and bone metastases to docetaxel treatment. These findings provide a rationale for targeting Ac-KLF5/CXCR4 signaling as a novel therapeutic strategy in advanced prostate cancer patients with bone metastases. Citation Format: Baotong Zhang, Yixiang Li, Qiao Wu, Lin Xie, Benjamin Barwick, Jin-Tang Dong. KLF5 acetylation promotes bone metastatic growth of prostate cancer by activating CXCR4/IL-11 and subsequent osteoclast differentiation [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 3840.
Diagnosing, managing and preventing anaphylaxis: Systematic review
Authors: Debra de Silva, Chris Singh, Antonella Muraro, Margitta Worm, Cherry Alviani, Victoria Cardona, Audrey DunnGlvin, Lene Heise Garvey, Carmen Riggioni, Elizabeth Angier, Stefania Arasi, Abdelouahab Bellou, Kirsten Beyer, Diola Bijlhout, M. Beatrice Bilo, Knut Brockow, Montserrat Fernandez‐Rivas, Susanne Halken, Britt Jensen, Ekaterina Khaleva, Louise J. Michaelis, Hanneke Oude Elberink, Lynne Regent, Angel Sanchez, Berber Vlieg‐Boerstra, Graham Roberts
Journal: Allergy (2020)

This systematic review used the GRADE approach to compile evidence to inform the European Academy of Allergy and Clinical Immunology's (EAACI) anaphylaxis guideline.We searched five bibliographic databases from 1946 to 20 April 2020 for studies about the diagnosis, management and prevention of anaphylaxis. We included 50 studies with 18 449 participants: 29 randomized controlled trials, seven controlled clinical trials, seven consecutive case series and seven case-control studies. Findings were summarized narratively because studies were too heterogeneous to conduct meta-analysis.It is unclear whether the NIAID/FAAN criteria or Brighton case definition are valid for immediately diagnosing anaphylaxis due to the very low certainty of evidence. There was also insufficient evidence about the impact of most anaphylaxis management and prevention strategies. Adrenaline is regularly used for first-line emergency management of anaphylaxis but little robust research has assessed its effectiveness. Newer models of adrenaline autoinjectors may slightly increase the proportion of people correctly using the devices and reduce time to administration. Face-to-face training for laypeople may slightly improve anaphylaxis knowledge and competence in using autoinjectors. We searched for but found little or no comparative effectiveness evidence about strategies such as fluid replacement, oxygen, glucocorticosteroids, methylxanthines, bronchodilators, management plans, food labels, drug labels and similar.Anaphylaxis is a potentially life-threatening condition but, due to practical and ethical challenges, there is a paucity of robust evidence about how to diagnose and manage it.
Abstract 6415: RAF dimer inhibitor lifirafenib enhances the antitumor activity of MEK inhibitor mirdametinib in RAS mutant tumors
Authors: Xi Yuan, Xinwen Zhang, Rong Du, Shing-Hu Cheung, Min Wei, Changyou Zhou, Lai Wang, Todd Shearer, Badreddin Edris, Mary Smith, Zhan Yao, Claire N. Thant, Neal Rosen, Lusong Luo
Journal: Cancer Research (2020)

Abstract K-RAS mutation represents one of the most frequent genetic alterations in cancers. Monotherapy approaches targeting RAS downstream effectors such as MEK and ERK have had limited clinical success in patients with K-RAS-mutated cancers. The reduced sensitivity of K-RAS-mutated cells to certain MEK inhibitors is associated with feedback phosphorylation of MEK and reactivation of mitogen-activated protein kinase (MAPK) signaling. Herein, we report that RAF dimer inhibitor lifirafenib (BGB-283) shows strong synergistic effect with MEK inhibitor mirdametinib (PD-0325901) in suppressing proliferation of K-RAS-mutated cancer cell lines. This synergistic effect was not observed using vemurafenib, a first-generation B-RAFV600E selective inhibitor. Mechanistic analysis revealed that RAF dimer inhibition could suppress RAF-dependent MEK reactivation and led to sustained inhibition of MAPK signaling in K-RAS-mutated cells. Furthermore, combination synergy was observed in K-RAS mutant xenograft models. Pharmacodynamic analysis supported the role of synergistic phospho-ERK blockade in enhancing the antitumor activity in the K-RAS mutant models. These findings support the rationale to combine a RAF dimer inhibitor and a MEK inhibitor to treat K-RAS-mutated cancers and led to the ongoing a Phase Ib/II clinical trial of lifirafenib and mirdametinib in patients with K-RAS mutations or other MAPK pathway aberrations (Clinical Trial ID: NCT03905148). Citation Format: Xi Yuan, Xinwen Zhang, Rong Du, Shing-Hu Cheung, Min Wei, Changyou Zhou, Lai Wang, Todd Shearer, Badreddin Edris, Mary Smith, Zhan Yao, Claire N. Thant, Neal Rosen, Lusong Luo. RAF dimer inhibitor lifirafenib enhances the antitumor activity of MEK inhibitor mirdametinib in RAS mutant tumors [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 6415.
Abstract 1083: Heterozygous knockout of the histone modifier MLL4 promotes Ptch+/−-driven medulloblastoma
Authors: Shilpa S. Dhar, Dongyu Zhao, Tao Lin, Roy V. Sillitoe, Kaifu Chen, Min Gyu Lee
Journal: Cancer Research (2020)

Abstract Medulloblastoma (MB) is the most common primary childhood brain tumor. MB development frequently results from the dysregulation of sonic hedgehog and wingless pathways. In contrast to our understanding of these pathways, the pathogenic roles of aberrant epigenetic modifiers in MB remain little known. MLL4 is one of the most commonly mutated genes in MB. In our recent study, we showed that brain-specific knockout of the gene encoding the histone H3 lysine 4 methyltransferase MLL4 (also called COMPASS-like methyltransferase, KMT2D, MLL2, and ALR) induced spontaneous MBs. Mll4 loss highly upregulated several oncogenic signaling programs, including expression of several oncogenic Ras activators (e.g., Rasgrp1, Rasgrf1, and Rasgef1a). In contrast, Mll4 loss downregulated expression of tumor-suppressive genes, such as Dnmt3a. In this study, we sought to determine whether Mll4 loss cooperates with other oncogenic event in MB genesis. Particularly, PTCH (also known as PTCH1) is one of the most frequently mutated genes in MB, and its loss induces MB in mouse models. Thus, we examined the effect of Mll4 loss on of Ptch+/−-driven MB genesis. A heterozygous loss of Mll4 increased the incidence and progression of Ptch+/−-driven MB genesis. MBs were confirmed by H &amp; E staining, and immunohistochemical staining using anti-Ki-67 showed that cell proliferation was markedly increased. Calbindin signals were undetectable in Nestin-Cre Mll4f/+ Ptch+/−, and NeuN levels were decreased in Nestin-Cre Mll4f/+ Ptch+/− cerebellum compared to Ptch+/− cerebellum, suggesting the impairment of Purkinje and granule cells. Mll4 loss reduced cerebellar granule cell differentiation. These findings indicate that a haploinsufficiency of MLL4 promotes Ptch+/−-driven MB genesis. This mouse model may be useful for future preclinical therapeutic experiments for the treatment of MB patients with MLL4 mutations. Citation Format: Shilpa S. Dhar, Dongyu Zhao, Tao Lin, Roy V. Sillitoe, Kaifu Chen, Min Gyu Lee. Heterozygous knockout of the histone modifier MLL4 promotes Ptch+/−-driven medulloblastoma [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 1083.
Abstract 2091: DeepBTS: Prediction of recurrence-free survival of non-small cell lung cancer using time-binned deep neural network
Authors: Ho Jung An, Bora Lee, Sang Hoon Chun, Ji Hyung Hong, In Sook Woo, Seoree Kim, Joon Won Jeong, Jae Jun Kim, Hyun Woo Lee, Sungsoo Park, Heejoon Jo, Yoon Ho Ko
Journal: Cancer Research (2020)

Abstract Introduction: Accurate prediction of non-small cell lung cancer (NSCLC) prognosis after surgery is still challenging. Cox proportional hazard model is widely used, but there are some limitations like proportional hazard assumption, computational complexity, and unspecified time component. In this study, we developed the novel neural network models using 30 clinicopathological features of surgically resected NSCLC patients. Materials and Methods: We analyzed a dataset of training cohorts of 1,034 patients and external validation cohort of 303 patients, and compared the novel neural network model and Cox PH model to predict 3-year recurrence of the patient. Results: We developed deep neural network for binned time survival analysis (DeepBTS) algorithm, which use root-mean-squared error (supervised learning model, s- DeepBTS) or negative log-likelihood (semi-unsupervised learning model, su- DeepBTS) as loss function. The su-DeepBTS algorithm showed the improved performance (C-index, 0.7166; AUC, 0.7606) compared to other models (Cox PH: 0.6861 and 0.7185; s-DeepBTS: 0.6926 and 0.7250, respectively). Top 10 features was selected from su-DeepBTS model and su-DeepBTS selector pair: the number of lymph node metastasis, tumor size, histologic subtype, vascular invasion, R0 resection, neoadjuvant /adjuvant treatment, and performance status of patients. These features distinguished low and high-risk group in the training cohort (p = 4.25×10-5) and the validation cohort (p = 1.07×10-11). Conclusions: The su-DeepBTS model using 10 selected features can predict the prognosis of resected NSCLC patients. We plan to diversify the input features by radiologic, pathological imaging and genomic data to integrate multimodal medical information and enhance the performance of this model using deep neural network. Citation Format: Ho Jung An, Bora Lee, Sang Hoon Chun, Ji Hyung Hong, In Sook Woo, Seoree Kim, Joon Won Jeong, Jae Jun Kim, Hyun Woo Lee, Sungsoo Park, Heejoon Jo, Yoon Ho Ko. DeepBTS: Prediction of recurrence-free survival of non-small cell lung cancer using time-binned 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 2091.
Abstract 3052: Targeting AXL in <i>PIK3R2</i>-amplified ovarian cancer
Authors: Ling Rao, Victor C. Mak, Yuan Zhou, Dong Zhang, Xinran Li, Yiling Lu, Gordon B. Mills, Lydia W. Cheung
Journal: Cancer Research (2020)

Abstract The p85 regulatory subunit and its associated p110 catalytic subunit are components of the class IA PI3K that mediates the downstream signal of receptor tyrosine kinases. PIK3R2 (encoding p85β, one of the p85 isoforms) is commonly amplified in ovarian cancer patients. Importantly, high PIK3R2 expression significantly correlated with worse patient survival. Here, we showed that p85β promoted tumorigenic properties of ovarian cancer cells. The protein expression of a receptor tyrosine kinase AXL was positively regulated by p85β. AXL is a member of the TAM receptor family. The regulation was specific to AXL because the other two members (Tyro3 and MERTK) were not altered by p85β. Drug sensitivity assays suggested that inhibition of AXL reduced oncogenic activities of p85β in vitro and in vivo. Together, we propose p85β as a potential therapeutic target in ovarian cancer and therapeutic blockade of AXL signaling may be an effective strategy for ovarian cancer with PIK3R2 amplification. Citation Format: Ling Rao, Victor C. Mak, Yuan Zhou, Dong Zhang, Xinran Li, Yiling Lu, Gordon B. Mills, Lydia W. Cheung. Targeting AXL in PIK3R2-amplified ovarian 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 3052.