tbuckley/cabot-search huggingface dataset:
Abstract 545: Prognostic alternative mRNA splicing signature in non-small cell lung cancer
Authors: Yuan Li, Nan Sun, Zhiliang Lu, Shouguo Sun, Jianbing Huang, Zhaoli Chen, Jie He
Journal: Cancer Research (2017)

Abstract Alternative splicing provides a major mechanism to generate protein diversity. Increasing evidence suggests a link of dysregulation of splicing associated with cancer. However, alternative splicing in non-small cell lung cancer (NSCLC) is largely unstudied. In this study, seven types of alternative splicing were profiled in 491 lung adenocarcinoma (LUAD) and 471 lung squamous cell carcinoma (LUSC) patients in TCGA using RNA sequencing data. Prognostic predictors for LUAD, LUSC and merged NSCLC patients were built by integrated survival analysis. Gene network and splicing correlation network analyses were also conducted. Overall, we detected 45,062 and 50,732 alternative splicing events in LUAD and LUSC, respectively, almost half of them were exon skipping events. A total of 3,691 and 2,403 alternative splicing events were significantly associated with patient survival in LUAD and LUSC, respectively. Gene network analysis uncovered important hub genes or nodes such as EGFR, CD44, PIK3C3, RRAS2, MAPKAP1 and FGFR2. The area under the curve (AUC) of the receiver-operator characteristic (ROC) curve for prognostic predictors in LUAD and LUSC were 0.960 and 0.940 at 2000 days of overall survival. Most relevant for clinical application, we also built the prognostic predictor for NSCLC patients with high performance. The AUC of ROC curve in NSCLC was 0.817 which were also over 0.8 in LUAD and LUSC, separately. Moreover, expression of 49 and 9 survival associated splicing factors were significantly correlated with 75 survival associated alternative splicing events in LUAD and LUSC, respectively. Interestingly, splicing correlation networks uncovered that “oncogenic“ splicing factors were up-regulated in LUAD while “tumor suppressor” splicing factors were down-regulated in LUSC. Survival associated splice factors might have opposite roles in the regulation of RNA splicing in LUAD and LUSC. In conclusion, we created prognostic predictors based on alternative splicing events with high performances for risk stratification in NSCLC patients and uncovered interesting splicing networks in LUAD and LUSC which could be underlying mechanisms. Citation Format: Yuan Li, Nan Sun, Zhiliang Lu, Shouguo Sun, Jianbing Huang, Zhaoli Chen, Jie He. Prognostic alternative mRNA splicing signature in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 545. doi:10.1158/1538-7445.AM2017-545
Abstract 5554: Metabolic reprogramming in non-small cell lung cancer: a precision oncology approach
Authors: Iman Tavassoly, Ravi Iyengar
Journal: Cancer Research (2017)

Abstract Lung cancers are among the most common invasive cancers worldwide and annually lead to high mortality and morbidity. Genomic alterations have been known to control the evolution of hallmarks of cancer in a dynamic way. These molecular alterations combined with epigenomic and post-genomic modifications contribute to formation of these neoplasms. Multiplicity of these changes has made development of personalized therapeutic regimens for these cancers a complex problem. Metabolic reprogramming is one of the main mechanisms in progression of cancers. There have been efforts to model the metabolic reprogramming in cancer using metabolic networks of cancer cells, but there has been no computational framework to model these metabolic transitions in cancer for precision and personalized medicine. We have combined computational, mathematical and experimental methodologies to develop a platform for precision oncology in non-small cell lung cancer (NSCLC) by in silico models of metabolic switches. Our integrative analysis of genomic data from NSCLC has led to discovery of genomic signatures controlling metabolic reprogramming in NSCLC with KRAS mutations. This discovery was proved in vivo and in vitro using drugs blocking different metabolic pathways. We have shown that NSCLC cells and tumors which carry KRAS mutations and have these genomic signatures are addicted to the pentose phosphate pathway (PPP). We have verified and proved the predictive value of these genomic signatures using Patient Derived Xenograft (PDX) tumor models of NSCLC. We are developing a mathematical and computational framework to model these metabolic switches. Our platform is capable of using genomic data from a cell line or tumor to determine the metabolic dependency of them quantitatively and predict the optimized personalized treatments for modulating metabolic pathways aiming to control cancer progression. Citation Format: Iman Tavassoly, Ravi Iyengar. Metabolic reprogramming in non-small cell lung cancer: a precision oncology approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5554. doi:10.1158/1538-7445.AM2017-5554
Abstract 4844: CRISPR-generated BAP1 knockdown in uveal melanoma cell lines affects organotropism
Authors: Katharina Mahal, Kelly Brooks, Amit Mandal, Matthew Smith, Nathalie Dhomen, Richard Marais
Journal: Cancer Research (2017)

Abstract Uveal melanoma (UM), a genetically distinct subtype of melanoma, arises from melanocytes located in the uveal tract of the eye, and is the most common intraocular cancer in adults. Clinically evident metastasis occurs in about 50% of patients, often several years after successful treatment of the primary tumour, with secondary disease occurring predominantly in the liver. In most cases surgical resection is not possible, and there are currently no effective chemotherapeutic treatments available once the metastatic disease has developed. Loss of the tumor suppressor and chromatin modifier BAP1 (BRCA1-associated protein 1) is linked with poor prognosis and high risk for developing liver metastasis. However, our knowledge about the processes involved in UM metastasis and the mechanisms that enable metastatic growth preferentially in the liver is limited. We recently described a panel of isogenic BAP1 knockout/knockdown UM cell lines generated by CRISPR technology, which allowed us to study the cellular effects of BAP1 loss in comparison to parental UM cell lines. In mouse xenograft studies we were able to show that BAP1-loss of function (LOF) promoted metastatic growth preferentially in the liver, while the parental cells metastasized mainly to lymph nodes and lung. A possible explanation for the observed liver tropism could lie in the alteration of protein secretion or receptor expression patterns upon BAP1 knockout that may result in an increased sensitivity to liver specific growth factors or cytokines. We are currently investigating gene expression and protein alterations resulting from BAP1 knockdown, and the reciprocal signaling between the CRISPR cell line pairs and liver cells such as hepatocytes and hepatic stellate cells in co-culture experiments. These studies will reveal a potential mechanism by which loss of BAP1 function mediates liver tropism in vivo and potentially provide new therapeutic avenues for patients at high risk of metastatic UM disease. Citation Format: Katharina Mahal, Kelly Brooks, Amit Mandal, Matthew Smith, Nathalie Dhomen, Richard Marais. CRISPR-generated BAP1 knockdown in uveal melanoma cell lines affects organotropism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4844. doi:10.1158/1538-7445.AM2017-4844
Abstract 2839: Systematic enrichment analysis of gene expression profiling studies identifies SPARC dependent consensus pathways implicated in bladder cancer
Authors: Bincy Anu John, Neveen Said
Journal: Cancer Research (2017)

Abstract Bladder cancer (urothelial cancer of the bladder) is the most common malignancy affecting the urinary system with increasing incidence and mortality. Treatment of bladder cancer has not advanced in the past 30 years. Therefore, there is a crucial unmet need for novel therapies, especially for advanced disease. We have recently reported Secreted Protein Acidic and Rich in Cysteine (SPARC) as a tumor suppressor in urinary bladder cancer that inhibits the multistep cascades on tumor initiation, progression and metastasis. SPARC gene and protein expression was among candidates associated with the tumorigenicity of the isogenic T24/T24t cell lines. We reported that SPARC depletion in human bladder cancer cell lines including T24 cells increased their tumorigenicity and metastatic potential. In addition, SPARC protein and transcript expression are significantly downregulated in advanced urothelial cancer. To gain insight on the molecular mechanisms of the tumor suppressor effects of SPARC in urothelial cancer, we did whole transcriptome profiling of T24 cells depleted of SPARC to identify SPARC-signature associated with bladder cancer invasiveness, progression, and metastasis. Subsequently, we used gene signature enrichment analysis (GSEA) pathway enrichment tools to define functionally related genes that are consistently up- or down- regulated as a function of loss of SPARC. We found that loss of SPARC expression is associated with enrichment of multiple oncogenic signaling pathways that are enriched in muscle invasive urothelial cancer and have been associated with poor prognosis. These pathways include K-ras, Myc-oncogene, p53 pathways as well as DNA damage/repair. Consistent with our earlier reports, loss of SPARC is associated with genes and proteins involved in angiogenesis, inflammation and hypoxia. In addition, we have identified novel signatures involved in unfolded protein response, mTOR signaling, glycolysis and cholesterol metabolism. These comprehensive signatures not only reveal SPARC-dependent networks that cooperate to elicit its biological responses but enables coherent understanding of the etiology of complex bladder cancer disease. Importantly, these signatures identify novel therapeutic opportunities for bladder cancer. Citation Format: Bincy Anu John, Neveen Said. Systematic enrichment analysis of gene expression profiling studies identifies SPARC dependent consensus pathways implicated in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2839. doi:10.1158/1538-7445.AM2017-2839
Corticosteroid Metabolism and Rheumatoid Arthritis
Authors: E. Bailey, M. S. Greaves, D. Murphy, H. F. West
Journal: Annals of the Rheumatic Diseases (1966)

It is generally held that cortisol (hydrocortisone) is metabolized in the liver (Peterson, Wyngaarden, Guerra, Brodie and Bunim, 1955;Bush, 1962).If this is the case the effective concentration of cortisol in all other tissues will be determined by its concen- tration in non-protein-bound (n-p-b) form in plasma.If, on the other hand, cortisol is metabolized by enzymes in extra-hepatic tissue cells, it is these enzymes that will be the final determinant of the effective concentration within such cells.It will be necessary therefore to study the activity of these enzymes in any diseased tissue (e.g.connective tissue) that is sensitive to small changes in the concentration of plasma cortisol.In this paper evidence will be presented for the existence of extensive extra-hepatic metabolism of cortisol and detail will be given of attempts made to detect abnormal extra-hepatic metabolism of cortisol and prednisolone in rheuma- toid arthritic patients.* Unknown.Each chromatogram is 20 cm.long.
Abstract 1649:In vivoCRISPR-Cas9 library screen for immune checkpoint regulators
Authors: Sascha Karassek, Min Long, Xi Li, Zhengang Peng, Qunsheng Ji, Yong Cang
Journal: Cancer Research (2017)

Abstract Therapeutic antibodies blocking immune checkpoints such as programmed cell death protein 1 (PD1) have proven clinically beneficial in multiple cancer types. However, anti-PD1 drugs approved by FDA are neither effective in treating all cancer types nor in all patients in a responsive cancer type. Therefore, understanding the mechanism underlying the efficacy of immune checkpoint blockade is critical for our rational design of synergistic treatment combinations. Here we describe how we employ the latest CRISPR-Cas9 genome-wide knockout screening strategies to identify targets in cancer cells or in T lymphocytes that control the sensitivity or resistance to anti-PD1 treatment. We constructed a sgRNA library targeting the functional domains of 116 mouse methyltransferases and demethylases, which was infected into the mouse Cloudman S91 melanoma cell line. Syngeneic mouse xenograft models derived from these infected cells were treated with anti-mPD1 monoclonal antibody, and the xenograft tumors were harvest at different time points after antibody treatment. Deep sequencing of the integrated sgRNA sequences in the tumors has identified potential druggable targets to sensitize or antagonize the tumors resistance to anti-mPD1 immunotherapy. Alternatively, we introduced the same library to naïve T cells purified from the OT-1 transgenic mice. The T cell library was then injected to B16-OVA melanoma syngeneic mouse models, followed by anti-mPD1 treatment. Deep sequencing of the integrated sgRNA sequences in the tumor-infiltrating T cells would allow us to uncover novel signaling molecules in the immune system that can potentially be manipulated to enhance the anti-PD1 therapy. In summary, we provide in vivo knockout screen strategies that can be applied to identify and validate combination therapies with immune checkpoint antibodies. Citation Format: Sascha Karassek, Min Long, Xi Li, Zhengang Peng, Qunsheng Ji, Yong Cang. In vivo CRISPR-Cas9 library screen for immune checkpoint regulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1649. doi:10.1158/1538-7445.AM2017-1649
Abstract 3648: Targeting glypican-2 in neuroblastoma via single domain antibody-based immunotoxins and chimeric antigen receptor T cells
Authors: Nan Li, Haiying Fu, Stephen Hewitt, Dimiter Dimitrov, Javed Khan, Mitchell Ho
Journal: Cancer Research (2017)

Abstract Neuroblastoma is the most common extracranial solid tumor in children. Approximately 45% of patients receiving standard therapy relapse and ultimately succumb to metastatic disease. One of the major challenges in the treatment of neuroblastoma and other pediatric cancers is the lack of effective targets. As such, there is an urgent need for a new therapeutic target. Here we demonstrate that glypican-2 (GPC2) protein is highly expressed in nearly half of neuroblastoma cases. High GPC2 expression has been correlated with poor overall survival when compared to patients with low GPC2 expression. The reduction of GPC2 expression inhibits neuroblastoma cell growth and induces tumor cell apoptosis through downregulation of Wnt/β-catenin signaling. We have discovered a group of human single domain antibodies specific for GPC2 and have used them to make two forms of antibody therapeutics, antibody-toxin conjugates (immunotoxins) and chimeric antigen receptor (CAR) T cells. Treatment with the immunotoxin inhibits proliferation of GPC2-positive neuroblastoma cells in vitro and mouse models. The CAR T cells targeting GPC2 suppress the growth of neuroblastoma xenograft tumors and eradicate disseminated neuroblastomas in mice. Our study establishes GPC2 as a new target of antibody-based cancer therapy and demonstrates that single domain-based antibody therapeutics can be used in the treatment of neuroblastoma. Citation Format: Nan Li, Haiying Fu, Stephen Hewitt, Dimiter Dimitrov, Javed Khan, Mitchell Ho. Targeting glypican-2 in neuroblastoma via single domain antibody-based immunotoxins and chimeric antigen receptor T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3648. doi:10.1158/1538-7445.AM2017-3648
Peroral endoscopic myotomy (POEM) in jackhammer esophagus: a trick of the trade
Authors: Enad Dawod, Monica Saumoy, Ming-Ming Xu, Michel Kahaleh
Journal: Endoscopy (2017)

A 69-year-old man presented for evaluation of progressive atypical chest pain. The patient noted 4 years of progressive daily chest pain, regurgitation of food, and intermittent dysphagia. After extensive evaluation, the patient underwent esophageal manometry which led to a diagnosis of jackhammer esophagus characterized by 100 % hypercontractile waves. The patient had minimal symptomatic response to amitriptyline. He was referred for peroral endoscopic myotomy (POEM).
Abstract 791: Inhibitory effects of theaflavin-3, 3′-digallate (TF3) on ovarian cancer cells
Authors: Yi C. Chen, Gary O. Rankin
Journal: Cancer Research (2017)

Abstract Theaflavin-3, 3'-digallate (TF3) is a black tea polyphenol produced from polymerization and oxidization of green tea ployphenols epicatechin gallate and (−)-epigallocatechin-3-gallate (EGCG) during fermentation of fresh tea leaves. TF3 has been reported to have anti-cancer properties. However, the effect of TF3 on tumor angiogenesis and the underlying mechanisms are not clear. In the current research, TF3 was verified to inhibit tumor angiogenesis. Compared with EGCG, TF3 was more potent. TF3 inhibited human ovarian carcinoma OVCAR-3 cells induced angiogenesis in human umbilical vein endothelial cell model and in chick chorioallantoic membrane model. TF3 reduced tumor angiogenesis by down-regulating HIF-1α and VEGF. One of the mechanisms was TF3 inactivated Akt/ mTOR/ p70S6K/ 4E-BP1 pathway and Akt/ c-Myc pathway. Besides, TF3 suppressed the cleavage of Notch-1, subsequently decreased the expression of c-Myc, HIF-1α and VEGF, and finally impaired cancer cells induced angiogenesis. Nevertheless, TF3 didn’t have any influence on MAPK pathways. Taken together, these findings suggest that TF3 might serve as a potential anti-angiogenic agent for cancer treatment. Citation Format: Yi C. Chen, Gary O. Rankin. Inhibitory effects of theaflavin-3, 3′-digallate (TF3) on ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 791. doi:10.1158/1538-7445.AM2017-791
Abstract 1542: Identifying genetic modifiers ofPTENusing the Collaborative Cross mouse panel
Authors: Amanda Lanier, William Barrington, David Threadgill
Journal: Cancer Research (2017)

Abstract Tumor suppressor genes code for proteins that limit cellular proliferation and cancer progression, and are often exploited in cancer therapies. One such tumor suppressor gene, Phosphatase and Tensin homolog deleted from Chromosome Ten (PTEN), mediates cell growth through negative regulation of phosphatidylinositol 3-kinase (PI3K) dependent pathways. PTEN is frequently deleted or mutated in a variety of human cancers. Mice carrying a PTEN transgene (Super-PTEN mice) were found to be resistant to tumor formation, and even small changes in PTEN expression and activity have been shown to influence cancer susceptibility and progression. We hypothesized that PTEN activity can be altered by modifier genes. To determine whether PTEN modifiers are influencing its activity, we are using the Collaborative Cross (CC), a panel of inbred mouse strains that has a similar amount of genetic variation as human populations. In CC-Super-PTEN crosses, we are utilizing an easily measured phenotype of Super-PTEN mice, reduced body weight, to identify CC strains with altered PTEN function. On average, weanlings carrying the PTEN transgene weigh 16% less than their wild type littermates, but this weight difference varies significantly across strains, from no weight reduction to as much as a 29% difference. This distribution of phenotypes has allowed us to use quantitative trait locus (QTL) mapping to identify potential modifiers of PTEN. Through association mapping, we have determined that the loci with the highest LOD scores reside on chromosomes 2, 12, 16, and X, and we are now reviewing genes within those loci to identify candidate modifiers of PTEN. Additionally, we are using several cancer models to determine the effects of said candidate genes and confirm that an altered PTEN weight phenotype correlates with changes in cancer susceptibility and progression. Ultimately, this research will demonstrate the use of the CC mouse panel to identify novel genetic modifiers and improve our understanding of PTEN regulation. Citation Format: Amanda Lanier, William Barrington, David Threadgill. Identifying genetic modifiers of PTEN using the Collaborative Cross mouse panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1542. doi:10.1158/1538-7445.AM2017-1542
Abstract 1962: Regulation of invasion by lysine demethylase 5B in non-small cell lung cancer cells
Authors: Elizabeth L. Zoeller, Jessica Konen, Joshua Bell, Emily Summerbell, Jeanne Kowalski, Adam Marcus, Paula Vertino
Journal: Cancer Research (2017)

Abstract Histone modifying enzymes are often dysregulated during carcinogenesis and are major contributors to the development of oncogenic features, including proliferation, drug resistance, and metastasis. Given these roles, histone modifiers are promising new targets for oncological therapeutics. One of the enzyme families at the center of this area of research is the lysine demethylase family KDM5, for which several inhibitors are in development. KDM5A and KDM5B are frequently overexpressed or mutated in human non-small cell lung cancer (NSCLC). In overexpression studies, KDM5B promotes invasion and migration of NSCLC cells, whereas invasion and migration of NSCLC cells were decreased following knockdown of KDM5B. Furthermore, in patients with NSCLC, KDM5B is expressed at higher levels in brain metastasis sites when compared to both normal tissues and primary tumors. These findings suggest a role for KDM5B in lung cancer and metastatic spread. However, the precise role of KDM5 family members in lung cancer invasion and metastasis is not known. Recently, we discovered that KDM5B is differentially expressed in cell subtypes within a 3D model of NSCLC collective cell invasion. In this model isolated single cells at the forefront of invasive branches (leader cells) express more 2-4 fold more KDM5B protein than the cells following (follower cells), while KDM5A and KDM5C are evenly expressed across both cell types. KDM5B mRNA expression is similar across cell types suggesting that the differential protein expression is mediated at the posttranscriptional level. Interestingly, global H3K4me3 levels are decreased in leader cells as compared to follower cells, supporting the idea that the lysine demethylases targeting this residue may be expressed at higher levels in leader cells. Collectively, these data suggest that KDM5B could be contributing to initiation of invasion at the primary site and thus, promoting metastasis. Given the rising prominence of therapeutic inhibitors of KDM5 family members, a better understanding how KDM5B contributes to cell invasion may lead to a new approach to the prevention of metastasis. Citation Format: Elizabeth L. Zoeller, Jessica Konen, Joshua Bell, Emily Summerbell, Jeanne Kowalski, Adam Marcus, Paula Vertino. Regulation of invasion by lysine demethylase 5B in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1962. doi:10.1158/1538-7445.AM2017-1962