tbuckley/cabot-search huggingface dataset:
Abstract 2589: Identifying cancer susceptibility variants and genes using whole exome and genome sequencing: a literature review
Authors: Melissa Rotunno, Mindy Clyne, Tram Lam, Leah Mechanic, Danielle Daee, Stefanie Nelson, Elizabeth Gillanders, Alisa Goldstein
Journal: Cancer Research (2017)

Abstract The application of Next Generation Sequencing (NGS) technologies in cancer research enabled the discovery of novel somatic mutations at an unprecedented speed through efficient high-throughput profiling of DNA variation in tumor samples. In contrast, the identification through NGS studies of germline variation associated with cancer has been more difficult and with limited consensus around best practices for study design and analytical techniques. We performed a review of the 2005-2016 PubMed English literature for genome-wide germline sequencing studies that were aimed at identifying new cancer susceptibility genes or variants. We extracted and summarized the experimental and analytical designs, methods and tools implemented in the selected literature together with their degree of success and limitations in identifying cancer susceptibility variants. About 80 in-scope publications were identified and examined in depth. The most studied cancer types were colorectal, breast, blood and lung and were investigated predominantly via whole exome sequencing (primarily using Illumina HiSeq) in familial cases of Caucasian ethnicity. Only 10 studies used whole genome sequencing and 15 adopted a case control study design. A large fraction of the familial studies was limited to 1 or 2 families and sequenced 2 or less cases per family. Reporting of key data quality information (e.g., human sequence coverage) was inconsistent throughout the publications. While the methods for sequence alignment and variant calling converged towards those implemented in established bioinformatic tools (e.g., BWA, GATK), there were no standard approaches for filtering or prioritizing of variants. Most studies included some degree of technical validation, often restricted to the top few variants or genes. About 60% of the studies included replication in an independent group of cancer patients and 55% functionally validated their findings to some extent. Our work provides valuable data and insights to inform future sequencing studies of cancer genetic susceptibility, and points to the need for improving standardization and completeness in reporting of quality control metrics, study design rationale and interpretation of findings. Citation Format: Melissa Rotunno, Mindy Clyne, Tram Lam, Leah Mechanic, Danielle Daee, Stefanie Nelson, Elizabeth Gillanders, Alisa Goldstein. Identifying cancer susceptibility variants and genes using whole exome and genome sequencing: a literature review [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 2589. doi:10.1158/1538-7445.AM2017-2589
Abstract 3922: NR2F1 limits dissemination and stemness of early breast cancer cells
Authors: Maria Soledad Sosa
Journal: Cancer Research (2017)

Abstract Tumor cells derived from MMTV-Neu mouse models or human ErBb2+ primary tumors are known to be able to complete all steps of the metastatic cascade. However, new evidence show that Neu+ early cancer cells derived from early stages of tumor progression (before detection of palpable tumors), can disseminate and, as disseminated cancer cells (early DCCs), enter a non-proliferative state for prolonged periods of time at secondary organs. We recently showed that early DCCs contributed to metastasis formation together with late-arriving DCCs (those coming from overt tumors). However, the mechanisms that would allow these early cancer cells, considered sessile and with few genetic alterations, to complete all steps of metastasis are unknown. Here we report that downregulation of the orphan nuclear receptor NR2F1 in Neu+ early cancer mammary epithelial cells (MECs) further activated a motile phenotype and this was coincident with previously described detection of circulating cancer cells (CCCs) and lung and bone marrow DCCs in MMTV-Neu mouse model. Knock down of basal NR2F1 levels in Neu+ early cancer cells induced cell motility, loss of laminin-V deposition, β-catenin delocalization from the membrane, dramatic loss of E-cadherin junctions and increased percentage of leader cells positive for CK14 and PRRX1 staining. Interestingly, TWIST and PRRX1 levels became upregulated upon NR2F1 depletion in 3D structures. These results suggest that NR2F1 expression maintains epithelial identity and suppresses epithelial-mesenchymal transition (EMT). Knock down of NR2F1 in Neu+ early cancer cells enhanced mammosphere formation efficiency and this was accompanied by upregulation of the pluripotency transcription factor NANOG and EMT master regulator TWIST. Interestingly, early dormant DCCs (negative for proliferation markers) showed re-expression of NR2F1 levels while micrometastases (cycling cells) had reduced levels of NR2F1. This result suggests that downregulation of NR2F1 in early DCCs may contribute to the dormancy escape of early DCCs and consequently metastatic relapse. Our findings provide for the first time evidence that NR2F1 functions as a suppressor of stemness and dissemination during early stages of tumor progression. We propose that therapies that restore expression of NR2F1 might limit early dissemination and the progression of early and late-arriving DCCs toward metastatic outgrowth. Citation Format: Maria Soledad Sosa. NR2F1 limits dissemination and stemness of early breast 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 3922. doi:10.1158/1538-7445.AM2017-3922
Abstract 1015: Directionality of T-cell-mediated cross-protection against the same tumor in lungs versus skin
Authors: Jessica J. O'Konek, Elena Ambrosino, Anja Bloom, Liat Izhak, Jay A. Berzofsky, Masaki Terabe
Journal: Cancer Research (2017)

Abstract Immunotherapy is a new pillar of cancer therapy. One theoretical advantage of immunotherapy of cancer is that effector cells induced at one site should be able to kill metastatic cancer cells in other sites or tissues. On the other hand, it has been recognized that each tissue has unique immune components that play critical roles in protection against pathogens. However, very little is known whether effector T cells induced against tumors in one tissue can work against the same tumors in other tissues. To address this question, we compared the effect of effector cells induced against the same tumor cells growing in either the skin or the lung by using CT26 murine tumor models. Rejection of s.c. CT26 tumors was achieved by pretreatment with anti-CD25, which blocks the function of Treg cells. Both CD4 and CD8 T cells were necessary for the protection. When anti-CD25-pretreated mice challenged with s.c. CT26 were simultaneously inoculated i.v. with CT26, they also rejected tumors in the lung, while anti-CD25-pretreated mice without s.c. CT26 did not. This observation suggested that T cell mediated anti-tumor protective immunity induced against s.c. tumors can also protect against lung metastases of the same tumors. In contrast to Treg depletion which allowed for the induction of protective immunity in the s.c. tumor model, NKT cell-deficiency in CD1d KO mice induced significant CD8 T cell-mediated protection against lung metastasis of CT26 but had no effect on the growth of s.c. CT26 tumors. When CD1d KO mice rejecting i.v. CT26 were simultaneously challenged with s.c. CT26, the development of s.c. tumors was not affected, indicating that tumor rejection induced against the CT26 in the lung did not confer protection for the same tumor cells in the skin. Since the protection against CT26 in the lung in CD1d KO mice is mediated by CD8 T cells, we transferred T cells from CD1d KO mice inoculated i.v. with CT26 into RAG1 KO recipients, and challenged the recipient mice with the CT26 tumor cells. The recipient RAG1 KO mice were highly resistant to CT26 inoculated i.v. but not s.c. confirming that the CD8 T cells protective in the lung are not protective in the skin. These data indicate the effector cells against the same tumor do not work in all tissues, and the induction site of the effector T cells is critical to control metastasis. Citation Format: Jessica J. O'Konek, Elena Ambrosino, Anja Bloom, Liat Izhak, Jay A. Berzofsky, Masaki Terabe. Directionality of T-cell-mediated cross-protection against the same tumor in lungs versus skin [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 1015. doi:10.1158/1538-7445.AM2017-1015
Abstract 2578: Investigating the role of mutant p53 in esophageal squamous cell carcinoma
Authors: Ashley Lento, Apple Long, Veronique Giroux, Qiaosi Tang, Morgan Sammons, Andres Klein-Szanto, Shelly Berger, Anil Rustgi
Journal: Cancer Research (2017)

Abstract Esophageal squamous cell carcinoma (ESCC) is a highly aggressive cancer characterized by a high rate of metastasis, limited therapeutic options, and a poor prognosis. However, there is limited information regarding the molecular mechanisms underlying the metastatic properties of ESCC. p53 is one of the most commonly mutated genes in ESCC, and our group has shown that esophageal cells lines expressing a mutation in human p53 shows signs of malignancy and increased invasion in 3D organotypic culture. A mouse model of mutant p53 (R172H) in ESCC is lacking in the field. To elucidate the role of mutant p53 in ESCC we developed a novel mouse model utilizing a genetic and carcinogenic approach. L2cre;p53-/- and p53R172H/- mice were generated and treated with 4NQO in their drinking water for 16 weeks, which resulted in the development of ESCC. Compared to wildtype mice, p53R172H/- mice and p53-/- mice exhibited a decreased tumor latency time, increased tumor frequency and a more severe tumor diagnosis. However, p53R172H/- mice and p53-/- mice displayed similar tumorigenic properties. RNA-seq was performed on cell lines established from wildtype and p53 mouse models and reveled different gene expression profiles between wildtype, p53R172H/-, and p53-/- cells. p53R172H/- cells displayed an increase in mesenchymal and decrease in epithelial marker expression, supporting the idea that they are undergoing EMT. In addition, several endocytic recycling related genes, including Rab11-fip1, Rab25, and Myo5b were downregulated in mutant and null p53 compared to wildtype cells. Further examination of the differing genetic profiles in our mouse models can provide novel insight into the role of mutant p53 in ESCC tumorigenesis and lead to the identification of new therapeutic targets. Citation Format: Ashley Lento, Apple Long, Veronique Giroux, Qiaosi Tang, Morgan Sammons, Andres Klein-Szanto, Shelly Berger, Anil Rustgi. Investigating the role of mutant p53 in esophageal squamous cell carcinoma [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 2578. doi:10.1158/1538-7445.AM2017-2578
Abstract 4547: Structural, thermodynamics and kinetics role of novel hot-spot mutations of BCR-ABL1 in resistance towards "Ibs" inhibitors
Authors: Erik Laurini, Domenico Marson, Silvia Boccardo, Maurizio Fermeglia, Sabrina Pricl
Journal: Cancer Research (2017)

Abstract The present contribution integrates structural, computational, and molecular biology techniques to understand the eventual role of our newly reported hot-spot mutations of the BCR-ABL1 KD in TKI resistance observed in CML patients (1) using a "two-tier level" investigation: isolated KDs and SH2-liker-SH3-KD BCR-ABL1 constructs. Specifically, in silico experiments will disclose the effects exerted by the “hot-spot” BCR-ABL1 mutations on the protein structure, thermodynamic stability, and ability to interfere with BCR-ABL1 binding to specific TKIs (e.g., imatinib, dasatinib, and ponatinib). Structural biology (e.g., SAXS) evidences of wild type and mutant isolated KDs and SH2-linker-SH3-KD (SSK) constructs (per se and in complex with TKIs) will be discussed to support in silico predictions. Direct drug binding thermodynamics and kinetics to both KD and SSK constructs will be measured using isothermal titration calorimetry and surface plasmon resonance. In vitro kinase assays will monitor the ability of these mutant isoforms to auto-phosphorylate and to phosphorylate a substrate peptide. (1) Gibbons DL, Pricl S, Posocco P, et al., Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3550-5. doi: 10.1073/pnas.1321173111 Note: This abstract was not presented at the meeting. Citation Format: Erik Laurini, Domenico Marson, Silvia Boccardo, Maurizio Fermeglia, Sabrina Pricl. Structural, thermodynamics and kinetics role of novel hot-spot mutations of BCR-ABL1 in resistance towards "Ibs" inhibitors [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 4547. doi:10.1158/1538-7445.AM2017-4547
Abstract 3843: Autologous resconstitution of human cancer and immune system in vivo
Authors: Juan Fu, Rupashree Sen, David L Masica, Rachel Karchin, Drew Pardoll, Young Kim
Journal: Cancer Research (2017)

Abstract Correlative studies from checkpoint inhibitor trials have indcated that better understanding of human leukocytic trafficking into the human tumor microenvironment can expedite the translation of future immune-oncologic agents. In order to directly characterize signaling pathways that can regulate human leukocytic trafficking into the tumor, we have developed a completely autologous xenotransplanation method to reconstitute the human tumor immune microenvironment in vivo. When we analyzed the TCGA database of human head and neck squamous cell carcinoma(HNSCC), we found that STAT3 signaling was associated with worse prognostic mesenchymal subtye. We silenced STAT3 signaling in the tumor compartment in these autologously reconstituted humanized mice, and we noted increased tumor infiltrating lymphocytes and slower tumor growth rate. We also used this novel agents that can alter endogenous leukocytic infiltration into the tumor. Taken together, we present a valuable method to study individialized human tumor microenvironments in vivo without confound allgeneic responses. Citation Format: Juan Fu, Rupashree Sen, David L Masica, Rachel Karchin, Drew Pardoll, Young Kim. Autologous resconstitution of human cancer and immune system in vivo [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 3843. doi:10.1158/1538-7445.AM2017-3843
Breast cancer extracellular matrix gene cluster: Association with prognosis and response to tamoxifen.
Authors: Jozien Helleman, Maurice Jansen, Anieta Sieuwerts, Iris van Staveren, Kirsten Ritstier, Maxime Look, Marion Meijer-van Gelder, Jan Klijn, John Foekens, Els Berns
Journal: Clinical Cancer Research (2007)

A6  Background: We previously identified an extracellular matrix (ECM) gene cluster from which the expression was associated with response to first-line tamoxifen therapy in metastatic breast cancer patients (Jansen et al J Clin Oncol 2006). This ECM gene cluster comprises six genes, collagen 1A1 (COL1A1), fibronectin (FN1), lysyl oxidase (LOX), secreted protein acidic cysteine-rich (SPARC), tissue inhibitor of metalloproteinase 3 (TIMP3) and tenascin C (TNC). In this study we determined the association of these ECM genes with response to tamoxifen monotherapy, metastatic potential, or both.  Methods: We have measured the ECM geneexpression levels by real-time polymerase chain reaction in 1,286 primary breast tumor specimens. Expression levels were normalized to housekeeper gene levels and were analyzed as continuous variables in relation to clinicopathologic factors for all patients. In addition, in a multivariate analysis the expression levels were compared to traditional prognostic and predictive factors (age, menopausal status, tumor size, grade, LN status, ER, PgR, dominant site of relapse and disease-free interval).  Results: TIMP3, FN1, LOX and SPARC expression was significantly associated with distant metastasis-free survival (MFS) in 680 lymph node negative untreated patients (p
Usefulness of a newly designed plastic stent for endoscopic re-intervention in patients with malignant hilar biliary obstruction
Authors: Takeshi Tomoda, Hironari Kato, Hirofumi Kawamoto, Shinichiro Muro, Yutaka Akimoto, Daisuke Uchida, Kazuyuki Matsumoto, Shigeru Horiguchi, Koichiro Tsutsumi, Hiroyuki Okada
Journal: Endoscopy (2017)

Abstract Background and study aims We designed a new 7-Fr plastic stent for treating self-expandable metal stent (SEMS) obstruction in patients with malignant hilar biliary obstruction (MHBO) via endoscopic re-intervention with the stent-in-stent (SIS) method and evaluated its efficacy. Patients and methods A total of 33 consecutive patients who underwent endoscopic re-intervention for metal stent obstruction after multi-branched SEMS placement were enrolled. The initial SEMSs were placed in two or three biliary branches in 14 and 19 patients, respectively. We retrospectively evaluated the technical and clinical success, and adverse events. Technical success was defined as successful plastic stent placement into all target branches through the lumen of the SEMS. Results The technical success rates were 85.7 % (12/14) and 78.9 % (15/19) in patients who underwent two- or three-branched biliary drainage, respectively. The clinical success rate was 100 % in the 27 patients in whom technical success was achieved. We achieved successful plastic stent placement in more than two branches, using the new plastic stent combined with a conventional plastic stent, in 97.0 % (32/33). Conclusions This new plastic stent was technically feasible for treating stent obstruction via re-intervention with SIS methods.
Basic Mechanisms of the Epilepsies.
Journal: Annals of Internal Medicine (1970)

Man', wrote William Lennox, 'is built to convulse'.The unique status of the ictus has fascinated every reflective physician since Hippocrates reluctantly confessed that epilepsy was a disease unlike any other.This volume seeks to describe those basic properties of brain that are thought to underlie seizures.Every neurologist will find something to read and to
Involvement of Allele-Specific Methylation of Asparagine Synthetase Gene in Asparaginase Sensitivity of BCP-ALL
Authors: Atsushi Watanabe, Takeshi Inukai, Minori Tamai, Tamao Shinohara, Shinpei Somazu, Hiroko Oshiro, Koshi Akahane, Kumiko Goi, Kunio Miyake, Kevin Urayama, Kanji Sugita
Journal: Blood (2016)
Abstract 967: Development of fluorescent-cell based high throughput assay to identify novel therapeutics of bladder cancer cells through upregulation of SPARC expression
Authors: Chirayu M. Patel
Journal: Cancer Research (2017)

Abstract Bladder cancer is the most common malignancy affecting the urinary system with an estimated 76,960 new cases and projected 16,390 deaths in 2016 in the United States. The role of SPARC in various cancers is contextual and differs based on the tumor classification, malignancy and progression. We have recently reported the tumor suppressor effect of SPARC in urinary bladder cancer. We have shown that the loss of SPARC in bladder cancer resulted accelerated bladder carcinogenesis and metastasis multiple pathways involving cell cycle deregulation, inflammation and angiogenesis. We have also reported that SPARC protein expression significantly decreased in the cancerous compartment in advanced human bladder cancer as well as in carcinogen-induced murine urothelial cancer. However, the mechanism of the downregulation of SPARC expression in cancer in general and in bladder cancer in particular is still unraveled. The purpose of our study is to develop a robust, high throughput assay to identify therapeutic candidates as regulators of SPARC expression in bladder cancer. We cloned SPARC promoter in a third generation lentiviral vector coupled with fluorescent GFP or mCherry fluorescent protein to quantitatively measure SPARC expression. We generated stable bladder cancer cell lines expressing SPARC expression in bladder cancer cell lines. UMUC3 bladder cancer cells were transduced with lentiviral vector to generate SPARC-promoter reporter system to screen regulators of SPARC expression. Reporter cells were plated in 96 well plates and treated with 10uM of FDA-approved and natural product drug libraries. Real time monitoring of changes in SPARC expression was done by measuring GFP fluorescence intensity using IncuCyte® ZOOM Live Imaging Analysis System. We identified drugs that consistently exhibited dosage-dependent augmentation or down-regulation of SPARC expression in UMUC3 cells. Our screens identified novel up-regulators of SPARC expression that are both standard of care and novel bladder cancer therapeutics. Our efforts produced an efficient robust assay to identify novel therapeutics and regulators of the tumor suppressor SPARC in the bladder cancer ecosystem that can be used in the adjuvant and neoadjuvant settings. Citation Format: Chirayu M. Patel. Development of fluorescent-cell based high throughput assay to identify novel therapeutics of bladder cancer cells through upregulation of SPARC expression [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 967. doi:10.1158/1538-7445.AM2017-967