tbuckley/cabot-search huggingface dataset:
Abstract 5524: Gene 33/Mig6 regulates apoptosis and the DNA damage response through independent mechanisms
Authors: Cen Li, Soyoung Park, Xiaowen Zhang, Leonard Eisenberg, Hong Zhao, Zbigniew Darzynkiewicz, Dazhong Xu
Journal: Cancer Research (2017)

Abstract Gene 33 (Mig6, ERRFI1) is an inducible adaptor/scaffold protein whose expression can be induced by both stress and mitogenic signals. It contains multiple domains for protein-protein interaction and is involved in a broad spectrum of cellular functions including cell proliferation, cell migration, cell apoptosis, and cell senescence. Many functions of Gene 33 are attributable to its ability to bind to the kinase domain of the EGFR family receptor tyrosine kinases thereby inhibiting their activities. Gene 33 also binds and activates tyrosine kinase c-Abl and is involved in other signing pathways such as NF-κB, HGF, and JNK. Growing evidence at the genetic, cellular, and animal levels indicates that Gene 33 functions as a tumor suppressor in the lung. Gene 33 has been shown to promote apoptosis. A recent study has linked this protein to the DNA damage response induced by hexavalent chromium [Cr(VI)]. In the current study we find that ectopic expression of Gene 33 strongly induces apoptosis by both activating the c-Abl/p73 pathway and inhibiting the EGFR/AKT pathways in BEAS-2B lung epithelial cells and A549 lung carcinoma cells. Surprisingly, ectopic expression of Gene 33 also triggers the DNA damage response in an ATM-dependent fashion and through pathways with and without association with apoptosis. We observed striking presence of Gene 33 in the nucleus and chromatin, which is in contrast with the belief that Gene 33 is an exclusively cytoplasmic protein. Our data show that chromatin localization of Gene 33 is partially dependent on the EBD motif of Gene 33, a domain required for interaction with EGFR and c-Abl. Our data also indicate that Gene 33 may regulate chromatin targeting of c-Abl and EGFR. Furthermore we find that both endogenous and ectopically expressed Gene 33 strongly interact with histone H2AX. Our data have revealed potential nuclear/chromatin-associated mechanisms that underline the function of Gene 33 in apoptosis and the DNA damage response. Citation Format: Cen Li, Soyoung Park, Xiaowen Zhang, Leonard Eisenberg, Hong Zhao, Zbigniew Darzynkiewicz, Dazhong Xu. Gene 33/Mig6 regulates apoptosis and the DNA damage response through independent mechanisms [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 5524. doi:10.1158/1538-7445.AM2017-5524
Abstract 1501: Sideroflexin4: A novel regulator of iron metabolism in ovarian cancer
Authors: Bibbin Paul, Miranda Lynch, Frank Torti, Suzy Torti
Journal: Cancer Research (2017)

Abstract The five year survival rate for women with ovarian cancer is 9-34%. This high mortality is due to late stage diagnosis, marginally effective treatment and frequent disease recurrence. Alterations in metabolism have been widely recognized as an important hallmark of cancer. Metabolism of the micronutrient iron is significantly altered in many cancers, including ovarian cancers. The expression of genes governing iron transport (TFR1 and FPN), iron storage (FTL and FTH) and iron regulation (IRP1 and IRP2) are significantly altered in ovarian cancer compared to normal ovarian epithelial cells, resulting in higher intratumoral iron retention. However, specific pathways of intracellular iron utilization that are altered in cancer cells, and the functional consequences of disrupting these pathways, remain poorly understood. To identify pathways of iron utilization that are perturbed in ovarian cancer, we analyzed the expression of genes involved in iron metabolism using a publicly available microarray database of ovarian cancer and normal oviduct (GSE69428). We observed that sideroflexin4 (SFXN4), an inner mitochondrial membrane protein that is essential for mitochondrial respiratory homeostasis, was significantly upregulated (p= 0.002) in ovarian cancer patient samples. We screened several ovarian cancer cell lines and observed that SFXN4 was similarly up-regulated both at the mRNA and protein level when compared to normal human ovarian surface epithelial cells. To test the role of SFXN4 in ovarian cancer cells we performed knockdown and overexpression studies. Knockdown of SFXN4 induced S and G2-phase cell cycle arrest and reduced the ability of MDAH2774 and SKOV3 ovarian cancer cells to form colonies. Further investigation revealed that modulation of SFXN4 alters mitochondrial respiration by affecting iron-sulfur cluster biogenesis. Thus, knock-out cells exhibited impaired respiratory activity and a phenotype similar to cells with defects in iron-sulfur cluster biogenesis, including increased IRP-IRE binding and a decrease in IRP1/ACO1 aconitase activity. Furthermore, SFXN4 knock-out decreased the activity of iron-sulfur cluster-containing enzymes such as mitochondrial aconitase and succinate dehydrogenase. Based on these observations, we postulate that SFXN4 acts as a molecular mediator that channels the excess iron present in ovarian cancer cells to iron-sulfur cluster-dependent metabolic pathways that favor growth and metastasis. SFXN4 may be a potential druggable target in ovarian cancer. Citation Format: Bibbin Paul, Miranda Lynch, Frank Torti, Suzy Torti. Sideroflexin4: A novel regulator of iron metabolism in ovarian 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 1501. doi:10.1158/1538-7445.AM2017-1501
Abstract 4442: micoRNA in FA defective tumor
Authors: Shirley Tang, Li Gao, Kathleen Kathleen, Andrew Fink, Arjun Kalvala, Brittany Aguila, Gregory Otterson, Miguel Villalona-Calero, Wenrui Duan
Journal: Cancer Research (2017)

Abstract The Fanconi Anemia (FA) pathway is essential for human cells to maintain integrity following DNA damage. This pathway is involved in the endogenous repair of double stranded DNA breaks and homologous recombination as well as repair of DNA cross-linking caused by exogenous agents. Cancers with defective FA pathway are expected to be more sensitive to cross-link based therapy, or to treatments in which additional repair mechanisms are targeted. We have recently reported the detection of up to 20% of NSCLC to be FA functionally inactive (lack of FANCD2 foci formation in the nucleus of proliferating cells by triple stain immunofluorescence, FATSI negative). MicroRNAs (miRs, miRNA) are small, 19-25 nucleotide, single stranded, non-coding RNA molecules that have regulatory roles in humans by targeting mRNAs via cleaved or translational repression which can affect the output of protein coding genes and cause various changes in developmental and physiological processes including cancer. It has been published that some miRNAs are tumor suppressors, and others are oncogenes. However, microRNAs and the FA pathway in relationship to lung cancer progression remain unknown. In order to elucidate the role of FA related miRs in human lung cancer development or treatment, we analyzed miR expression in lung cancer cells and patient lung tumors. Several cell lines were generated using RNAi technology with FANCD2 deficiency and confirmed via reduction in FANCD2 protein expression. Using Nanostring counter technology, microRNA array analysis was performed on FANCD2 foci positive and foci negative tumors as well as matching normal lung tissues. A cluster of microRNAs (mir-431, 377, 376c, 200c, 26a, 135a, and let-7e) were found to be up-regulated, and miR-494,205, 630, 145,671 were found to be down-regulated in the foci negative tumors samples compared to matching non-tumor lung tissue. The same group of miRs were upregulated and its corresponding group were down-regulated in the foci negative tumors as compared to foci positive tumors. These findings indicate that the FA pathway may regulate downstream genes through regulation of microRNAs in lung cancer. In order to validate this hypothesis, specific miRs were be analyzed with Real-Time Quantitative PCR via foci positive and foci negative samples (cell and patient tissue) in hopes of finding significant and consistent regulation. This study contributes to further understanding in miRNA and cancer pathology that may be applicable to futuristic lung cancer treatment. Citation Format: Shirley Tang, Li Gao, Kathleen Kathleen, Andrew Fink, Arjun Kalvala, Brittany Aguila, Gregory Otterson, Miguel Villalona-Calero, Wenrui Duan. micoRNA in FA defective tumor [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 4442. doi:10.1158/1538-7445.AM2017-4442
INJURIES IN AMERICAN YOUTH RUGBY-7S: AN EMERGING ADOLESCENT COLLISION SPORT
Authors: Victor Lopez, Richard Ma, Meryle Weinstein, Patria Hume, Robert Cantu, Christian Victoria, Sophie Queler, Allen Answorth
Journal: British Journal of Sports Medicine (2017)

Background Rugby-7s growth in the United States predominantly seen in the amateur population, has very little youth rugby injury data. Objective To report incidence and causes for US youth Rugby-7s match injuries. Design Prospective descriptive epidemiology study. Setting The study encompassed Under-19 players in USA Rugby sanctioned tournaments (2010–2014). Participants A total of 3,804 US players (13–19 years old) were included over 24 tournaments, of 643 youth-division matches (140=female; 515=male) in 317 sides/teams (61=females; 256=males). Assessment of Risk Factors Causes in youth Rugby-7s injuries. Main measurement outcome Injury incidence (per 1000 player-hour (ph)) and mechanism, captured using Rugby Injury Survey &amp; Evaluation ( RISE ) Report methodology. Time-loss injuries=players who did not return to play the day of their injury. Medical attention injuries=players who had injuries evaluated with no absence from play. Severity=days absent before return to training/competition (including post tournament). Results Injuries combined were found at 81.9/1000 ph (n=172) (time-loss injuries=33.3/1000 ph; n=70; medical attention injuries=48.6/1000 ph; n=102; P =0.013). Males among positions, experienced higher rates of injuries (backs 81.8/1000 ph, n=77; forwards 56.7/1000 ph, n=40; RR: 1.16, P =0.053) than females (backs 65.6/1000 ph, n=17; forwards 77.1/1000 ph, n=15; RR: 0.93, P=0.642) (RR: 0.96, P =0.332). Time-loss injuries resulted in a mean severity of 35.4 days (females, 29.6 days; males, 37.6 days). Most injuries were acute (93%; RR: 2.3, P &lt;0.001) during tackling (80.3%; RR: 1.6, P &lt;0.001). Injuries most commonly involved the joints or ligaments (40%) and the lower extremities (39%). High incidences of head and neck injuries including concussions (overall 26%) and upper extremity injuries (29%) were seen among the youth. Conclusions US Rugby-7s youth had lower time-loss injury rates (33.3/1000 ph) than US amateur adult Rugby-7s (49.2–55.4/1000 ph) and international boys' Rugby-15s (35–57.2/1000 ph). Due to tackling injuries among head, neck and upper extremity, US youth would benefit from injury prevention in a tackling technique evaluation.
Abstract 546: Supporting neoantigen identification for personalized cancer vaccines trough analytical validation of an augmented content enhanced (ACE) transcriptome
Authors: Jennifer L. Yen, Sean Boyle, Ravi Alla, Jason Harris, Martina Lefterova, Richard Chen
Journal: Cancer Research (2017)

Abstract The identification of neoantigens has become a critical step in the development of neoantigen-based personalized cancer vaccines and other immunotherapy applications. Since neoantigens can be generated from tumor specific mutations in any expressed gene, the first step in neoantigen identification typically involves deep sequencing of the tumor exome and transcriptome combined with exome sequencing of the matched normal. As personalized vaccines enter clinical trials, there is a growing need for strong analytical validation of these platforms. To address this, we have developed the ACE Exome (~200X) and Transcriptome platforms for neoantigen identification which harness an augmented exome approach specifically designed to increase sensitivity for neoantigens in low complexity, difficult to sequence regions. To enable this platform for neoantigen based personalized cancer vaccines, we have performed a validation of both our ACE Exome (tumor and normal) and ACE transcriptome platforms for detecting DNA-based SNVs and Indels, as well as for RNA based small variant and fusion calls, variant types that are especially important for neoantigen identification. In this abstract, we describe the ACE Transcriptome validation. To validate the ACE Transcriptome, we assessed analytical sensitivity (AS) and positive predictive accuracy (PPA). AS was calculated from a reference set of 894 SNVs and 19 indels across 11 tumor cancer cell lines with matched normals. The reference set was constructed based on previously observed variants in CCLE, COSMIC or had been validated by Sanger sequencing. PPA and limit of detection (LOD) were calculated in a series of tumor-normal dilutions representing allele frequencies ranging from 10% to 100%. For fusions, we further selected an additional 10 cell lines to test the detection of 16 previously characterized fusion events including several clinically actionable fusions (ALK and BCR-ABL1). We report an analytical sensitivity for SNVs of &amp;gt;99%, and a PPA of &amp;gt;96% for small variants with &amp;gt;=10% minor allele frequency (MAF). For fusion events, we report an analytical sensitivity of &amp;gt;99%, with the detection of all 16 fusion events supported by at least 5 reads. We demonstrate that our ACE Transcriptome assay and RNA cancer pipeline is a highly sensitive and robust platform for detecting small variants and fusions in the RNA. Citation Format: Jennifer L. Yen, Sean Boyle, Ravi Alla, Jason Harris, Martina Lefterova, Richard Chen. Supporting neoantigen identification for personalized cancer vaccines trough analytical validation of an augmented content enhanced (ACE) transcriptome [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 546. doi:10.1158/1538-7445.AM2017-546
Abstract 2921: Integrated exome- and single cell RNA-sequencing reveals a clone's genomic instability and multifaceted fitness
Authors: Noemi Andor, Carlo C. Maley, Hanlee P. Ji
Journal: Cancer Research (2017)

Abstract DNA-damage therapy is the main line of defense against most cancers, especially at advanced stages of progression. DNA-damage therapy damages the cell’s DNA. We have identified that a cell’s cumulative extent of DNA damage - even when successfully repaired - is an indicator for future tolerance to new insults. This finding points to a quantitative measure of genomic instability as biomarker of sensitivity to DNA-damaging agents. However, quantifying genomic instability is difficult, especially because each individual tumor harbors clones with their own distinct genomic characteristics. Here we address the challenge of quantifying the complex phenotype of genomic instability across the clonal subpopulations that coexist within an individual tumor. We identified coexisting clones from bulk-exome sequencing and calculated the copy number profile of each clone’s genome. We integrated mutations detected in both, single-cell RNA-sequencing (scRNA-seq) and exome sequencing, to assign single cells to clones. Because cells in G2/M phase of the cell cycle (further referred to as G2/M clones) have twice the ploidy compared to cells in other cell cycle phases, their presence represents an opportunity for validation. Using 15 gastric cancer cell lines - each sorted by cell cycle phase - we validated: i) clone-specific copy number and ii) assignment of single cells to clones. Here, the predicted size of G2/M clones is an indicator of how correct we quantify clone-specific copy number. The degree to which expression of cell cycle genes is exclusive to G2/M clones is an indicator as to how correct we assign single cells to clones. In addition to the dominant quiescent clone and the G2/M clone, we identified other discrete subclones in a subset of cell lines, suggesting that genetic intra-tumor heterogeneity is sometimes maintained in-vitro. This approach identified clone-specific markers that can be used for cytometry separation of cells of specific clonal subpopulations. Overall, we demonstrate the power of combining exome sequencing and scRNA-seq to reveal how many clones are present in a tumor sample, how genomically unstable each clone is and how fit is each clone. When combined, these two techniques synergize into a powerful strategy to investigate the relationship between genomic instability, clone fitness and DNA-damage sensitivity. Citation Format: Noemi Andor, Carlo C. Maley, Hanlee P. Ji. Integrated exome- and single cell RNA-sequencing reveals a clone's genomic instability and multifaceted fitness [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 2921. doi:10.1158/1538-7445.AM2017-2921
Abstract 5184: Radiosensitizing effect of lapatinib in HER2-overexpressing breast cancer cells: scientific rationale for RTOG1119 study
Authors: Tosol Yu, Bong Jun Cho, Eun Jung Choi, Ji Min Park, Dan Hyo Kim, In Ah Kim
Journal: Cancer Research (2017)

Abstract Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, however, it cannot easily cross the blood-brain barrier (BBB) and is known to increase the incidence of brain metastases. In contrast, lapatinib has a low molecular weight and can cross the BBB and it could be useful to treat brain metastases in patients with HER2-positive breast cancer. To explore the impact of lapatinib on radiation response, we conducted an in vitro experiment using SKBR3 and BT474 breast carcinoma cells exhibiting HER2/neu amplification. Lapatinib down-regulated phosphorylated p-HER2, p-EGFR, p-AKT, and p-ERK. Pretreatment of lapatinib increased the radiosensitivity of SKBR3 (sensitizer enhancement ratio [SER]: 1.21 at a surviving fraction of 0.5) and BT474 (SER: 1.26 at a surviving fraction of 0.5) cells and hindered the repair of DNA damage, as suggested by the prolongation of radiation-induced γH2AX foci and the down-regulation of phosphorylated DNAdependent protein kinase, catalytic subunit (p-DNAPKcs). Increases in radiation-induced apoptosis and senescence were suggested to be the major modes of cell death induced by the combination of lapatinib and radiation. Furthermore, lapatinib did not radiosensitize a HER2- negative breast cancer cell line or normal human astrocytes. These results suggest that lapatinib can potentiate radiation-induced cell death in HER2-overexpressing breast cancer cells and may increase the efficacy of radiotherapy. Based on these findings, RTOG1119 study which is a phase II randomized study for lapatinib combined with radiation therapy in patients with brain metastases from HER2-positive breast cancer is ongoing (NCT 01622868). Citation Format: Tosol Yu, Bong Jun Cho, Eun Jung Choi, Ji Min Park, Dan Hyo Kim, In Ah Kim. Radiosensitizing effect of lapatinib in HER2-overexpressing breast cancer cells: scientific rationale for RTOG1119 study [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 5184. doi:10.1158/1538-7445.AM2017-5184
Abstract 3501: Prognostic value of a 4 lncRNA signature in patients with non-small cell lung cancer: a lncRNA expression analysis
Authors: XiaoRan Long, HuiYun Wang, ChunLei Ge, Xin Song, MeiYin Zhang, XiaoFeng Zhen
Journal: Cancer Research (2017)

Abstract Recently, increasing evidence indicates that lncRNA plays an important role in the cancer development and progression. In this study, we are aimed to identify lncRNA signature for predicting survival of non-small cell lung cancer (NSCLC) patients. A total of 366 NSCLC cases, which were divided into a training and validation set, were detected by lncRNA microarray (containing 2412 lncRNA probes), and another 73 cases as an independent set were analyzed by qRT-PCR. LncRNA microarray analysis identified a total of 305 differentially expressed lncRNAs (138 up-regulated and 167 down-regulated) between NSCLC and normal tissues in the training set. We then validated the microarray data by qRT-PCR analysis of 5 lncRNAs (2 up-regulated and 3 down-regulated) in 30 paired NSCLC and adjacent lung tissues randomly selected from the training set. We then used a stepwise forward process to select the best combination of lncRNAs with the most significance in prediction of NSCLC prognosis and a 4-lncRNA prognostic signature was established, which was significantly associated with overall survival (hazard ratio [HR]: 3.563, 95% confidence interval [CI]: 2.118-5.995, P &amp;lt;0.001) and disease-free survival (HR: 3.236, 95% CI: 2.116-4.940, P &amp;lt;0.001) in the training set. This prognostic signature was validated in the validation (OS, HR: 3.186, 95% CI: 1.849-5.488, P &amp;lt;0.001; DFS, HR: 2.967, 95% CI: 1.949-4.517, P &amp;lt;0.001) and independent sets (OS, HR: 4.703, 95% CI: 1.923-11.50, P &amp;lt;0.001; DFS, HR: 4.549, 95% CI: 2.139-9.674, P &amp;lt;0.001). This 4-lncRNA signature has been demonstrated as an independent prognostic factor, which significantly improves the prognostic accuracy of TNM staging system in a combined model as assessed by ROC curve analyses in the three sets, respectively. Therefore, the 4-lncRNA signature has potential prognostic role in NSCLC patients. Citation Format: XiaoRan Long, HuiYun Wang, ChunLei Ge, Xin Song, MeiYin Zhang, XiaoFeng Zhen. Prognostic value of a 4 lncRNA signature in patients with non-small cell lung cancer: a lncRNA expression analysis [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 3501. doi:10.1158/1538-7445.AM2017-3501
Low-Density Lipoprotein Cholesterol Treatment in the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Era
Authors: Marc S. Sabatine, Robert P. Giugliano
Journal: JAMA Cardiology (2017)

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