tbuckley/cabot-search huggingface dataset:
Abstract 4256: Impact of diesel engine exhaust exposure on the airway transcriptome
Authors: Eduard I. Drizik, Sean Corbett, Roel Vermeulen, Yufei Dai, Wei Hu, Marc Lenburg, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, JuFang Yang, Meng Ye, Xiaowei Jia, Tao Meng, Ping Bin, Yuxin Zheng, Debra Silverman, Nathaniel Rothman, Avrum Spira, Qing Lan
Journal: Cancer Research (2017)

Abstract Rationale: Recent epidemiological studies show that Diesel Engine Exhaust (DEE) exposure is associated with lung cancer, however the mechanism by which this occurs is not well understood. The goal of this study was to assess the transcriptomic alterations in the nasal epithelium of DEE exposed workers from factories where diesel engines are utilized. Methods: Nasal epithelium brushings were obtained from 41 subjects who work in a factory with DEE exposure, and 38 comparable control subjects who work in factories without any DEE exposure. The median Elemental Carbon (EC) levels of exposed individuals was 60.7μg/m3, with a range of 17.2-105.4 μg/m3, respectively. RNA was isolated from nasal epithelial cells, and profiled for gene expression using Affymetrix microarrays. Linear modeling was used to detect differential expression between DEE exposure and controls. Pathway enrichment in differentially expressed genes was assessed using GO Biological Process and KEGG terms via EnrichR. Results: We found 234 genes that were differentially expressed between samples derived from DEE exposed participants versus controls at FDR q &amp;lt; 0.25. Within this set of genes, we observed a higher expression of genes involved in oxidative stress response, as well as cell proliferation, cellular transcription, and regulation of apoptosis. In addition, we found that genes involved in ion transport, such as CFTR, were expressed at lower levels in DEE exposed samples. Conclusions: Chronic DEE exposure associates with changes in the airway transcriptome, with increased stress response as a major effect of DEE exposure. The transcriptomic alterations we identified may help provide insight into the underlying mechanisms of DEE carcinogenicity. Citation Format: Eduard I. Drizik, Sean Corbett, Roel Vermeulen, Yufei Dai, Wei Hu, Marc Lenburg, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, JuFang Yang, Meng Ye, Xiaowei Jia, Tao Meng, Ping Bin, Yuxin Zheng, Debra Silverman, Nathaniel Rothman, Avrum Spira, Qing Lan. Impact of diesel engine exhaust exposure on the airway 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 4256. doi:10.1158/1538-7445.AM2017-4256
Abstract 1371: Isoprenylcysteine carboxylmethyltransferase (ICMT) function is critical for epithelial malignant transformation by mutant-Ras
Authors: Hiu Yeung Lau, Jingyi Tang, Patrick J. Casey, Mei Wang
Journal: Cancer Research (2017)

Abstract Purpose Limited progress has been made in the development of direct inhibitors of Ras. Therefore, targeting isoprenylcysteine carboxylmethyltransferase (ICMT), the final enzyme in the prenylation pathway for Ras and other proteins containing the so-called CaaX-motif, remains an important strategy to inhibit Ras function in cancers. In this study, we investigate the role ICMT plays in the initiation of human epithelial cancers involving constitutively-active mutant Ras using genetic manipulation strategies. Methods Small T antigen and a shRNA against p53 (shp53) were sequentially expressed in human mammary epithelial cells immortalized by hTERT (HME1-hTERT) to create pre-malignant HME1-shp53 cells. All 4 isoforms of wild-type or mutant Ras, namely H-Ras, N-Ras, K-Ras-4A and K-Ras-4B, were independently introduced into HME1-shp53 cells to determine their transforming ability. Using CRISPR-Cas9 genome editing technology, ICMT-null HME1-shp53 cells were generated and mutant Ras isoforms were subsequently introduced; tumor formation abilities of thus generated cells were determined using soft-agar anchorage-independent colony formation assay and subcutaneous xenografts in mice. ICMT knock-out was also performed in MiaPaCa-2 and MDA-MB-231 cells, both expressing mutant K-Ras, and subcutaneous xenograft tumor formation in mice was measured. Results Pre-malignant HME1-shp53 cells can be transformed by all mutant Ras isoforms but not by any wild-type Ras. ICMT loss-of-function dramatically reduced anchorage-independent colony formation caused by all mutant Ras isoforms in HME1-shp53 cells, and in vivo xenograft formation was completely abolished. ICMT loss-of-function also dramatically reduced in vivo xenograft formation for mutant K-Ras-expressing MiaPaCa-2 and MDA-MB-231 naturally-occurring cancer cells. Conclusion ICMT function is essential for the malignant transformation of HME1 cells by all isoforms of Ras. Furthermore, ICMT function is also crucial for the maintenance of the malignant phenotype in mutant K-Ras-expresing cells such as MiaPaCa-2 and MDA-MB-231 cells. Citation Format: Hiu Yeung Lau, Jingyi Tang, Patrick J. Casey, Mei Wang. Isoprenylcysteine carboxylmethyltransferase (ICMT) function is critical for epithelial malignant transformation by mutant-Ras [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 1371. doi:10.1158/1538-7445.AM2017-1371
Abstract 4682: Genomic profiles in gene expression and methylation help define the molecular characteristics of hairy cell leukemia subtypes
Authors: Daniel C. Edelman, Holly S. Stevenson, Yonghong Wang, Evgeny Arons, Joshua J. Waterfall, David Petersen, Hong Zhou, Paul S. Meltzer, Robert J. Kreitman
Journal: Cancer Research (2017)

Abstract Hairy cell leukemia (HCL) until recently was characterized as a single blood and bone marrow malignancy, even though clinically at least two pathologies seemed to be at work. This study sought to confirm the clinical observations using genomic evidence. HCL is a chronic mature B-cell malignancy with distinctive immunophenotype, typically expressing CD20, CD22, CD25, CD11c, CD103, CD123, annexin A1 (ANXA1), and tartrate-resistant acid phosphatase (TRAP). Purine analog therapy is highly effective, with most patients achieving durable remissions. HCL- variant (HCLv) was first identified by Cawley et al. (1980) and recently recognized by the World Health Organization as a separate cancer. HCLv lacks CD25, ANXA1, TRAP, and BRAF V600E expression, and patients respond poorly to purine analogs. In order to find detailed biological information involving these two diseases, we studied the genome-wide gene expression and methylation profiles of 75 HCL patient samples; 67 were tested by both methods. Our study results indicate that HCL and HCLv show very distinct gene expression and methylation patterns. Many genes that are differentially expressed are involved in immunological and inflammatory response pathways. Several cancer associated genes such as ANXA1 and FLT3 are down-regulated in HCLv compared to HCL. Correlation patterns between methylation and gene expression for many genes such as ANXA1 suggest that methylation plays an import role in gene expression regulation for these malignancies. This study has begun the process of identifying better biomarkers for disease discrimination between HCL and HCLv and providing potential new targets for strongly needed therapies for HCLv. Citation Format: Daniel C. Edelman, Holly S. Stevenson, Yonghong Wang, Evgeny Arons, Joshua J. Waterfall, David Petersen, Hong Zhou, Paul S. Meltzer, Robert J. Kreitman. Genomic profiles in gene expression and methylation help define the molecular characteristics of hairy cell leukemia subtypes [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 4682. doi:10.1158/1538-7445.AM2017-4682
Association Between Birth in a High Stroke Mortality State, Race, and Risk of Dementia
Authors: Paola Gilsanz, Elizabeth Rose Mayeda, M. Maria Glymour, Charles P. Quesenberry, Rachel A. Whitmer
Journal: JAMA Neurology (2017)

Birth in a group of predominantly southern US states is robustly linked to increased stroke risk. Given the role of cerebrovascular disease in dementia risk, geographic patterning may also occur for dementia incidence.To determine whether birth in 9 high stroke mortality states (HSMSs) is associated with dementia in a diverse cohort of individuals living in Northern California.An observational cohort study included 7423 members of Kaiser Permanente Northern California (KPNC), an integrated health care delivery system, with health survey and clinical examination data available. Data were collected between 1964 and 1973 when the individuals were middle-aged and 1996 and 2015 when participants were in later life.Self-reported state of birth in an HSMS (top quintile of states for stroke mortality).Dementia diagnoses obtained from electronic health records from January 1, 1996, to October 15, 2015. Place of birth, race, educational level, and midlife vascular risk factors data were collected between 1964 and 1973.Of the 7423 persons included in the analysis, 4049 (54.5%) were women; 1354 (18.2%) were black. The mean (SD) age of study participants at their first visit between 1963 and 1974 was 42.94 (1.73) years and mean (SD) age at the beginning of follow-up for dementia in 1996 was 71.14 (2.72) years. Dementia was diagnosed in 2254 (30.4%) of the participants and was more common among those born in an HSMS than those born outside of one (455 [39.0%] vs 1799 [28.8%]). Birth in an HSMS was 9.6 times more common for black participants (795 [58.7%]) than nonblack participants (371 [6.1%]). Overall, birth in an HSMS was associated with a 28% higher risk of dementia (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.13-1.46) adjusted for age, sex, and race. Compared with nonblack persons born outside of an HSMS, black individuals born in an HSMS had the highest dementia risk (aHR, 1.67; 95% CI, 1.48-1.88), followed by black individuals not born in an HSMS (aHR, 1.48; 95% CI, 1.28-1.72), and nonblack persons born in an HSMS had a 46% increased risk (aHR, 1.46; 95% CI, 1.23-1.74). Cumulative 20-year dementia risks at age 65 years were 30.13% (95% CI, 26.87%-32.93%) and 21.80% (95% CI, 20.51%-22.91%) for individuals born in and outside an HSMS, respectively.To our knowledge, this is the first study to date of place of birth and incident dementia and shows increased risk for individuals born in an HSMS, even though all participants subsequently resided in California. Birth in an HSMS was common among black participants. Place of birth has enduring consequences for dementia risk and may be a major contributor to racial disparities in dementia.
Abstract 1124: Assessment of HRD score as predictor of chemosensitivity of PDAC PDX xenograft models to DNA-damaging chemotherapy
Authors: Vladimir Khazak, Natalia Skobeleva, Anastasiia Vetkina, Ilya Serebriiskii, Kirsten M. Timms, Angela Davies, Igor Astsaturov
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals annually in the US, with almost 90% lethality even when diagnosed prior to metastasis. There is an urgent unmet medical need both for new therapies as well as better matching of existing therapies to patients. To address this emergency, we are assessing the feasibility of implementing a strategy of using HRD (Homologous Recombination Deficiency) scores for better therapy matching in PDAC patients. Using a panel of 77 patient-derived xenograft (PDX) models that were developed from fresh surgical PDAC tumor samples, HRD scores were generated based on analysis of three biomarkers (LOH, TAI and LST) and mutational data for 45 genes. All 77 samples met inclusion criteria, 75 FFPE specimens generated mutation data. HRD analysis was successful for 71 specimens (range= 1 - 63 (median=22)), with the primary cause of failure identified as high non-tumor content. 53 PDX models had mutations in KRAS gene and 45 in TP53. We have also identified 4 PDX models with mutations in BRCA2, 3 models with mutations in ATM, 4 models with mutations in RAD51. We have also found frequent mutations in several other DNA repair genes (ATR, PALB2, MLH1, MSH2, MSH3, MSH6, FANCM), but most of these models retained one functional allele and were not associated with a high HRD score. Using this genomic analysis, all 71 PDX models were stratified into three clusters with high, medium and low HRD scores. Three PDX models with the highest and lowest HRD scores each were selected for an in vivo study with DNA-damaging platinum-based chemotherapeutic agents Cisplatin and Carboplatin, as well as with a clinically relevant PARP inhibitor Niraparib. The results of the PDX study will be reported and compared with responses to chemotherapy using RECIST V1.1 in patients. Note: This abstract was not presented at the meeting. Citation Format: Vladimir Khazak, Natalia Skobeleva, Anastasiia Vetkina, Ilya Serebriiskii, Kirsten M. Timms, Angela Davies, Igor Astsaturov. Assessment of HRD score as predictor of chemosensitivity of PDAC PDX xenograft models to DNA-damaging chemotherapy [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 1124. doi:10.1158/1538-7445.AM2017-1124
Abstract 5079: Inhibition of HDAC2, but not HDAC1, abrogates triple negative breast cancer progression and metastasis
Authors: Hope E. Burks, Steven Elliott, Van T. Hoang, Margarite D. Matossian, Bridgette Collins Burow, Matthew E. Burow
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with higher rates of metastasis and recurrence than other classified subtypes. The decreased survival rates seen in TNBC can be attributed in part to the lack of targeted therapeutics. HDAC inhibitors (HDACi) have emerged as a potential adjuvant therapy for patients with triple negative disease. Previously, our lab has identified Panobinostat, a pan-DAC inhibitor, as a successful therapy for the reversal of the metastatic phenotype in TNBC. However, this therapy lacks specificity and may have increased side effects as a result. In this study, we aim to dissect the necessary HDACs responsible for driving and maintaining the metastatic phenotype of TNBC, with the goal of informing specific HDAC targeted therapies. Here we show that Romidepsin, an HDAC 1 and 2 specific inhibitor, is capable of recapitulating aspects of Panobinostat treatment in TNBC both in vitro and in a patient derived xenograft model in vivo. To parse the necessity and role of HDAC1 and HDAC2 individually, we created knockdown cell lines and analyzed them for changes in gene expression changes and their respective associated biological processes, including proliferation, migration, mammosphere formation, tumor growth and metastasis. We found that HDAC2 knockdown was able to significantly repress migration and proliferation in TNBC cells and their associated gene expression signatures in vitro. Furthermore, HDAC2 knockdown resulted in decreased tumor growth and metastasis an in vivo mouse model. These results illustrate the efficacy of Romidepsin in inhibition of oncogenic processes and implicate HDAC2 as a potential target for therapeutic intervention in TNBC. Citation Format: Hope E. Burks, Steven Elliott, Van T. Hoang, Margarite D. Matossian, Bridgette Collins Burow, Matthew E. Burow. Inhibition of HDAC2, but not HDAC1, abrogates triple negative breast cancer progression and metastasis [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 5079. doi:10.1158/1538-7445.AM2017-5079
Abstract 4074: Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of brain metastases of breast cancer
Authors: Afroz Shareef Mohammad, Chris E. Adkins, Neal Shah, Rawaa Aljammal, Jessica Griffith, Paul R. Lockman
Journal: Cancer Research (2017)

Abstract Background: Brain metastases vasculature is compromised and more permeable than that of vasculature in normal brain. Unfortunately, little is known about vascular permeability changes in brain adjacent to tumor (BAT). It is critical to understand the potential changes as chemotherapy penetration and accumulation brain tumors positively correlate with breakdown of the brain vasculature. Herein, we evaluate quantitatively measure permeability, drug accumulation and cytotoxicity in normal brain that is adjacent (&amp;lt;500 microns) to a tumor. Methods: The subclone population of brain seeking metastatic breast cancer cells (MDA-MB-231Br) were injected into the left ventricle of female NuNu mice. Mice were given a chemotherapeutic regimen of vinorelbine (10mg/kg), erubilin (1.5mg/kg) or docetaxel (10mg/kg). Progression occurred until neurological compromise was noted, at which time animals were injected with texas red 625 Da(TR) and texas red dextran 3kDa (TRD). Dye concentrations (measuring passive permeability changes) were determined in lesions and the BAT using quantitative fluorescent microscopy. Chemotherapeutic induced cytotoxicity was observed by staining for activated astrocytes and DNA damage in neurons, glia and endothelia. Results: We observed permeability of TR is highly heterogeneous both within and between the tumors (normal brain Kin TR: 1.2 x10-5)with 2-40-fold increase in permeability over normal brain region. TR concentrations in BAT (100µm from tumor edge) is consistently 40% of the tumor but significantly higher than that of normal brain and TR permeability in BAT increased 1-2.5-fold over normal brain. The permeability of TRD in tumor increased 2.7- 8.4-fold over normal brain, whereas in BAT, the permeability increased 1-1.6-fold over normal brain. We also observed animals treated with chemotherapy showed activated astrocytes in BAT, along with some cellular death. In vehicle treated animals there were little activated astrocytes and little cell death in the BAT. Conclusions: Our data suggests that the tracer and drugs accumulate in regions around tumors in the brain which result in neurotoxic changes. Citation Format: Afroz Shareef Mohammad, Chris E. Adkins, Neal Shah, Rawaa Aljammal, Jessica Griffith, Paul R. Lockman. Permeability changes and effect of chemotherapy in brain adjacent to tumor in an experimental model of brain metastases of breast 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 4074. doi:10.1158/1538-7445.AM2017-4074
Abstract 506: The role of Nek2 in hepatocellular carcinoma
Authors: Chan Shing Ho Vincent
Journal: Cancer Research (2017)

Abstract Cancer is a disease of aging. Among different types of cancer, liver cancer is one of the most prevalent cancers over the world and particularly affects people in some East Asia countries such as Korea, Japan and China. The NIMA-related kinase 2 (Nek2), which regulates centrosome cohesion, is a potential player in carcinogenesis. Our evidence showed Nek2 mRNA and protein levels are overexpressed in liver cancer cells and promotes HCC cell growth. Since Nek2 is pertinent to centrosome, we speculated that it might take part in centrosome regulation. To study the effect of Nek2 in chromosomal instability, centrosome splitting and cell cycle, a stable isoform Nek2A overexpression inducible system was generated in different Hepatocellular Carcinoma cell lines for investigations through immunofluorescent staining and cell-cytometry. For the study of centrosome, we observed that higher proportion of cells with centrosome splitting occurred in the Nek2A overexpressing cells in both HepG2 and SMMC-7721 inducible cell lines. Moreover, cell cycle analysis showed an increased content of DNA when Nek2A is overexpressed, suggesting that Nek2A induces more aneuploidy cells. To conclude, overexpression of Nek2 exacerbates chromosomal instability. Dysregulation of centrosome may be the key for understanding of regulatory mechanism of chromosomal instability by Nek2. Citation Format: Chan Shing Ho Vincent. The role of Nek2 in hepatocellular 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 506. doi:10.1158/1538-7445.AM2017-506
Abstract SY32-01: The new genetics and treatment of CLL
Authors: Carlo M. Croce
Journal: Cancer Research (2017)

Abstract Loss of miR-15/16 on chromosome 13q14 is the most common genetic alteration in CLL. Recently, we discovered that miR-15/16 target BCL2, an antiaptoptic gene we discovered and named in 1984. Thus, loss of miR-15/16 leads to overexpression of BCL2 (the driver) and causes sensitivity of CLL cells to the antiBcl2 drug venetoclax that is capable of inducing complete remission of CLL in patients and was approved by the FDA in April 2016. The discovery of the involvement of miR-15/16 in CLL also indicated that alterations in genes not encoding proteins can cause cancer. Before our publication of 2002, the dogma was that alterations in protein coding genes, oncogenes, and suppressor genes, cause cancer. We speculate that by looking at other targets of miR-15/16 we might discover other biomarkers that are overexpressed because of miR-15/16 loss, providing novel opportunities to discover targetable targets. Since it seems likely that among the billions of leukemic cells in patients, there are a few that do not respond to the drug—for example, because of mutations in the Bcl2 pocket binding the drug—it is important to develop other drugs capable of killing CLL cells because they have lost miR-15/16. We propose to define whether loss of miR-15/16 may lead to overexpression of specific surface markers that can be targeted by specific monoclonal antibodies. The availability of these antibodies will allow the killing of the same leukemic cells by using a combination of the antibodies and venetoclax minimizing the possibility of drug resistance. Finally, we will assess the role of a new family of short noncoding RNAs we have discovered, ts-RNAs, in the pathogenesis of CLL. Citation Format: Carlo M. Croce. The new genetics and treatment of CLL [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 SY32-01. doi:10.1158/1538-7445.AM2017-SY32-01