tbuckley/cabot-search huggingface dataset:
Abstract 1975: The 3D chromatin structure of the PTHLH region comprises a dynamic hierarchical looping complex that approximates the protein-coding genes and facilitates promoter and enhancer promiscuity
Authors: Adam N. Freeman, Michael A. Henderson, Miroslaw K. Kapuscinski, John Hopper, T John Martin
Journal: Cancer Research (2016)

Abstract Parathyroid Hormone-Like Hormone (PTHLH) is an important regulatory gene encoding the product Parathyroid Hormone-related Protein (PTHrP). Among many biological roles, it has been demonstrated to be essential to the development of multiple tissue-types, the regulation of foetal calcium levels, and the metastasis of breast cancer to bone. Its region has GWAS associations with breast cancer, breast size, height, type 2 diabetes mellitis, neural development, cardiac arrest, and several immunological phenotypes. They extend both up- and down-stream of PTHLH, however their driving molecular mechanisms remain obscure. Analysis of datasets including Hi-C, ChIA-PET, IM-PET and ChIP-seq suggests PTHLH sits within a 1.3Mb Topologically Associating Domain (TAD) containing 4 other protein-coding genes (pc-genes) CCDC91, MRPS35, MANSC4 and KLHL42. PTHLH itself rests between two 220kb inducible sub-TADs that likely comprise regulatory archipelagos directed primarily at its regulation. There are several other inducible loops in the TAD. All protein-coding genes within the TAD feature an Activated Chromatin Hub (ACH) nearby their 5’. The 3D-structure of the TAD appears to be supported by a system of permanent and dynamic tether points producing primary and inducible chromatin loops. These result in all pc-genes’ ACHs being 30 to 60kb from each other. RNA Pol II (RNAPII) ChIA-PET data suggests there is an inclusive hierarchical regulatory structure within the TAD, with substantial interaction between the ACHs of respective pc-genes that is likely facilitated by the 3D conformation. Citation Format: Adam N. Freeman, Michael A. Henderson, Miroslaw K. Kapuscinski, John Hopper, T John Martin. The 3D chromatin structure of the PTHLH region comprises a dynamic hierarchical looping complex that approximates the protein-coding genes and facilitates promoter and enhancer promiscuity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1975.
Evaluation of gene expression signatures induced by stromal factors as a predictor of survival in breast cancer.
Authors: I. Luehr, A. Klein, H. Pospisil, C. Standfuss, T. Kunze, F. Hilpert, C. Mundhenke, W. Jonat, M. Bauer
Journal: Journal of Clinical Oncology (2010)

10607 Background: Recent findings present the tumor microenvironment as an innovative therapeutic target in contrast to traditional tumor cell directed therapy. Fibroblasts have been identified to play an important role in breast cancer progression. We analyzed the effect of normal mammary fibroblasts on gene expression in human breast epithelial cells in a 3D coculture and it's correlation to clinical data. Methods: Nonmalignant HMT3522 S1 human breast epithelial cells were cultured in 3D collagen gels as mono- or coculture with normal human mammary fibroblasts. Gene expression profiles of S1 cells from co- and monoculture were analyzed using the Affymetrix HG-U133 Plus 2.0 GeneChip. Signal values were calculated by means of RMA using R Bioconductor 2.4, then log2 transformed. Transcripts with a log ratio ≥ ± 1.5 were defined as differentially expressed. Using published microarray profiles of 295 human breast tumors with associated clinical data t- tests, hierarchical cluster and Kaplan-Meier analysis were performed to stratify the patients according to the generated gene expression profiles. Results: S1 cells in 3D coculture differentiated into polarized acinus like structures and underwent growth arrest after 10 d of culture, whereas S1 cells in 3D monoculture showed unorganized and progressive growth. 99 transcripts were upregulated in S1 cells from co-compared to monoculture. Known functions of these genes mainly relate to extracellular matrix constitution and differentiation. 36 transcripts were upregulated in S1 cells from monoculture, predominantly involved in cell cycle regulation. Hierarchical cluster analysis stratified the patients into poor and good prognosis groups. Further on, Kaplan-Meier analysis showed that 21 selected genes were highly informative in identifying patients with poor or good outcome (p < 0.01). Conclusions: Gene expression changes in human breast epithelial cells induced by normal mammary fibroblasts provide gene expression profiles that clearly stratify patients into prognostic groups. Our 3D culture model proves to be a valuable in vitro model for cancer research and emphasizes the relevance of the tumor microenvironment as a target for breast cancer therapy. No significant financial relationships to disclose.
Abstract 3362: Expression of CD44v9, a cancer stem cell marker, in human hepatocellular carcinoma
Authors: Fumitaka Wada
Journal: Cancer Research (2016)

Abstract Background: CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration. This protein has recently been identified as one of the crucial cell surface markers for cancer stem cells (CSCs) in several types of tumor. It has recently been reported that CD44 variant 9 (CD44v9) interacted with the glutamate-cystine transporter xCT, thereby contributing to increased intracellular synthesis of glutathione (GSH), a strong scavenger of reactive oxygen species (ROS). CSCs having such mechanism are highly resistant to ROS (Cancer Cell 2011). Of note, the function of xCT is inhibited by sulfasalazine (Leukemia 2001), a commonly used drug for ulcerative colitis. Aim: The aims of this study were to assess 1) the expression levels of CD44v9 and xCT in human HCC tissues and HCC cell lines, and 2) possible synergistic anti-tumor effect of cisplatin and sulfasalazine on HCC cells. Methods: Thirty HCC tissues were subjected to immunohistochemistry for CD44v9 and xCT. The human HCC cell lines HAK-1A and HAK-1B were used. HAK-1B was an aggressive sister cell line derived from HAK-1A, a well-differentiated one (Hepatology 1993). The cells were incubated with cisplatin with or without sulfasalazine at concentrations of 0, 50, 100, and 200 μM under attached and sphere-forming conditions. Western blot analysis was employed to evaluate protein expression levels. Results: Membranous localization of CD44v9 was found in 2 HCC tissues, that were moderately and poorly differentiated ones. In such cases, the standard isoform CD44s was also strongly expressed. Expression levels of xCT were ubiquitously demonstrated in all HCC cases studied; however, it was robustly upregulated in sphere-formed HAK-1B cells, in concert with the upregulation of CD44v9 in these cells. Sphere formation of HAK-1B was significantly inhibited by co-treatment with cisplatin and sulfasalazine in a dose-dependent manner. Conclusions: The CD44v9-xCT system was demonstrated in less differentiated HCC tissues. Indeed, poorly differentiated HCC cells (HAK-1B) under sphere formation robustly expressed both CD44v9 and xCT, suggesting that CSC-like cells favored this system. To overcome the ROS resistance of CSCs, delivering sulfasalazine in combination with anti-cancer drugs may open a new avenue to a promising treatment of chemorefractory HCC. Citation Format: Fumitaka Wada. Expression of CD44v9, a cancer stem cell marker, in human hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3362.
Coadministration of a Plasmid Encoding HIV-1 Gag Enhances the Efficacy of Cancer DNA Vaccines
Authors: Laure Lambricht, Kevin Vanvarenberg, Ans De Beuckelaer, Lien Van Hoecke, Johan Grooten, Bernard Ucakar, Pascale Lipnik, Niek N Sanders, Stefan Lienenklaus, Véronique Préat, Gaëlle Vandermeulen
Journal: Molecular Therapy (2016)

DNA vaccination holds great promise for the prevention and treatment of cancer and infectious diseases. However, the clinical ability of DNA vaccines is still controversial due to the limited immune response initially observed in humans. We hypothesized that electroporation of a plasmid encoding the HIV-1 Gag viral capsid protein would enhance cancer DNA vaccine potency. DNA electroporation used to deliver plasmids in vivo, induced type I interferons, thereby supporting the activation of innate immunity. The coadministration of ovalbumin (OVA) and HIV-1 Gag encoding plasmids modulated the adaptive immune response. This strategy favored antigen-specific Th1 immunity, delayed B16F10-OVA tumor growth and improved mouse survival in both prophylactic and therapeutic vaccination approaches. Similarly, a prophylactic DNA immunization against the melanoma-associated antigen gp100 was enhanced by the codelivery of the HIV-1 Gag plasmid. The adjuvant effect was not driven by the formation of HIV-1 Gag virus-like particles. This work highlights the ability of both electroporation and the HIV-1 Gag plasmid to stimulate innate immunity for enhancing cancer DNA vaccine immunogenicity and demonstrates interesting tracks for the design of new translational genetic adjuvants to overcome the current limitations of DNA vaccines in humans.
Abstract 3461: Smoking cessation following a limited 5A intervention in a cohort of patients with head and neck cancer attending for treatment at a regional cancer program in Ontario, Canada
Authors: Michael S.C. Conlon, Deborah P. Saunders
Journal: Cancer Research (2016)

Abstract A smoking cessation intervention at the time of cancer treatment is an important opportunity to improve patient quality of life, treatment outcome, and survival in people with cancer. This prospective observational study was designed to assess intention to quit, motivation to quit, smoking characteristics and interest in smoking cessation, and assessment of cessation following a standardized smoking cessation intervention. The intervention was a limited clinical 5A intervention offered by trained health professionals and occurred within a dental oncology clinic that offered regular follow-up and any needed pharmacotherapy through the course of cancer treatment. The cohort was composed of head and neck cancer patients who were self-reported ever-smokers at enrolment and who attended the Northeast Cancer Centre, a regional cancer centre in Northeastern Ontario, Canada, for cancer treatment. There were 377 cancer patients who participated in study, with 35.8% (n = 135/377) self-reporting as current smokers. Most current smokers had high nicotine dependence, with 82.2% (n = 111/135) reporting a time to first cigarette (TTFC) of 30 minutes or less; 84.4% (n = 114/135) were interested in quitting smoking. By 1 year post intervention 10 patients had died and 28 patients were lost to follow-up; of the remainder 29 smokers had cessated yielding a cessation rate of 29.9% (n = 29/97); or 23.2% (n = 29/125) conservatively assuming those lost to follow-up remained current smokers. Offering comprehensive smoking cessation during the course of cancer treatment yields long term smoking cessation benefits in a cohort of patients with smoking associated cancers. Citation Format: Michael S.C. Conlon, Deborah P. Saunders. Smoking cessation following a limited 5A intervention in a cohort of patients with head and neck cancer attending for treatment at a regional cancer program in Ontario, Canada. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3461.
Differences in somatic DNA damage repair (DDR) gene alterations between primary and secondary muscle invasive bladder cancer (MIBC).
Authors: Eugene J Pietzak, Aditya Bagrodia, Qiang Li, Hikmat Al-Ahmadie, Harry W. Herr, Samuel Funt, David Barron, Ahmet Zehir, Michael F. Berger, David B. Solit, Maria E. Arcila, Dean F. Bajorin, Jonathan E. Rosenberg, Bernard H. Bochner, Eugene K. Cha, Gopa Iyer
Journal: Journal of Clinical Oncology (2016)

4519 Background: Alterations in DDR genes, including the nucleotide excision repair gene ERCC2, have been shown to be associated with response to systemic chemotherapy in MIBC (Van Allen, 2014). We hypothesized that patients with initial non-invasive bladder cancer treated with intravesical BCG who progress to “Secondary” MIBC (S-MIBC) would have fewer DDR gene alterations, than patients initially presenting with “Primary” MIBC (P-MIBC). Methods: Using data from TCGA and an institutional genomic research database of 545 patients, we identified 33 patients with S-MIBC and matched them by stage, gender, and age to 76 P-MIBC patients (Discovery set). We then validated our findings in a prospective cohort of 89 consecutive patients sequenced on an institutional clinical protocol with a CLIA-certified targeted exon-capture assay; 23 with S-MIBC and 66 with P-MIBC. Somatic alterations in DDR genes were compared between S-MIBC and P-MIBC tumors. Results: Patient demographics were evenly distributed in both the Discovery and Validation sets (Table). Within the Discovery set, somatic mutations in ERCC2 occurred in 20% of P-MIBC tumors (15/76), but were absent in S-MIBC tumors (0/33) (p = 0.01). No differences were seen in other DDR genes. These results were confirmed in our validation set, as 18% of P-MIBC tumors (12/66) had ERCC2 mutations, but none of the S-MIBC tumors (0/23, p = 0.03). Conclusions: Somatic ERCC2 mutations occurred frequently in P-MIBC tumors (19%, 27/142), but were absent in S-MIBC tumors (0/56), suggesting that tumors progressing to muscle invasive disease after intravesical BCG may be less likely to respond to systemic chemotherapy. Discovery Cohort Validation Cohort S-MIBC P-MIBC p = S-MIBC P-MIBC p = N = 33 76 23 66 Median Age (IQR) 68 (63, 76) 73 (66, 78) 0.2 67 (60, 74) 64 (56, 70) 0.3 Male 82% 79% 0.8 91% 88% 0.9 Stage 0.4 0.1 T2 45% 34% 52% 63% T3 36% 51% 39% 29% T4 18% 14% 9% 9% Node Positive 39% 42% 0.5 44% 36% 0.6 Metastasis 0 0 48% 39% 0.6 ERCC2 0 15 (20%) 0.01 0 12(18%) 0.03 Any DDR Gene 9 (27%) 31 (41%) 0.4 5 (22%) 20 (30%) 0.6 ERCC3 1 0 0 0 ERCC4 0 0 1 1 ATM 2 7 2 5 BRCA1 1 2 0 1 BRCA2 3 4 1 2 FANCA 1 1 0 1 FANCC 2 2 0 0 ATR 1 2 1 1 CHEK2 2 3 0 1 MSH2 1 0 0 0 MSH3 0 1 0 0 MSH6 1 0 0 1 POLE 1 2 0 1
Abstract 4082: Epithelial-stromal interactions are altered at the earliest stages of colon cancer development
Authors: Allen Mo, Stephen Jackson, Kamini Varma, Alan Carpino, Charles Giardina, Thomas J. Devers, Daniel W. Rosenberg
Journal: Cancer Research (2016)

Abstract While progression of nonmalignant colonic cells carrying somatic mutations to early malignancy is dependent upon interactions between mutated epithelium and surrounding stroma, the nature of these interactions is poorly understood. Here we report the development of an ultra-sensitive laser capture microdissection/RNA-seq approach for profiling the epithelial and stromal compartments of mutated aberrant crypt foci (ACF). ACF are the earliest detectable pre-neoplastic lesion found in human colon and were identified using high-definition endoscopy with contrast dye-spray. We focused on epithelial and stromal cells of ACF carrying somatic mutations to either KRAS, BRAF or APC, and compared these to control samples from each patient. By comparing the gene expression from each group, we identified an increase in a number of pro-inflammatory NF-κB target genes that are specific to ACF epithelium (including TIMP1, RELA and RELB). We confirmed distinct transcriptional changes associated with each somatic mutation and demonstrate that a subset of ACF display a BRAFV600E-mediated senescence-associated transcriptome, characterized by increased expression of CDKN2A (p16). Furthermore, ACF-associated stroma is transcriptionally distinct from adjacent normal stroma and genes related to immune cell infiltration and activation of fibroblasts are up-regulated. Immunofluorescence analysis confirms the abundance of activated fibroblasts in ACF stroma regardless of mutational status. These results provide new insight into the cellular interplay that occurs at the very early stages of colon cancer development, highlighting the role of activated stromal fibroblasts and inflammation. Citation Format: Allen Mo, Stephen Jackson, Kamini Varma, Alan Carpino, Charles Giardina, Thomas J. Devers, Daniel W. Rosenberg. Epithelial-stromal interactions are altered at the earliest stages of colon cancer development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4082.
Taxane use and neuropathy in early-stage breast cancer patients: Results from a U.S. community oncology center.
Authors: G. H. Volas-Redd, L. Chen, L. Zhao, B. A. Feinberg, J. W. Gilmore, S. Haislip, S. D. Sullivan, N. P. Christiansen
Journal: Journal of Clinical Oncology (2010)

e16522 Background: Neuropathy (NP) caused by taxane therapy can reduce quality of life of patients, interrupt scheduled chemotherapy (CT) and may result in compromised treatment effectiveness. A randomized trial comparing doxetaxel (D) and paclitaxel (P) treated patients has shown greater neurologic toxicity with P given weekly. The objective of this study was to compare NP and NP-related outcomes between D and P in a real-world practice setting. Methods: The Georgia Cancer Specialist Database (2003-2008) supplemented by chart review was used. Patients with breast cancer (BC) stage I-III and treated with adjuvant D or P containing CTs were selected. Patients were followed from initial CT to the earliest of death, loss to follow-up, or switch to other regimens. NP and NP-related outcomes were measured as (1) 6-month rate of severe NP (Chemotherapy toxicity criteria, grade 3 or 4), (2) 6-month rate of patients receiving NP-related medications (NPMs), (3) proportion of patients whose CT was affected due to NP (CT being held, discontinued, or dose reduction). In univariate analyses, outcome (1) and (2) were compared between D and P with Kaplan-Meier curves, and (3) was compared with Chi-square test. In multivariate analyses with adjustment of demographic and clinical factors, Cox models were used for outcome (1) and (2), and logistic model was used for (3). Results: The study sample included 591 (63.6%) and 338 patients treated with D and P, respectively. It was found that P, compared with D group (all p < 0.001), had higher 6-month rates of severe NP (4.9% vs. 1.0%) and NPMs use (28.1% vs. 7.6%), as well as was more likely to have their CT being affected (7.1% vs. 1.5%). Similarly, multivariate analyses demonstrated increased risks for severe NP (hazard ratio = 3.50) and NPMs use (hazard ratio = 6.40), as well as CT being interrupted (odds ratio = 5.40), associated with P compared with D group. Conclusions: This study found in a US local oncology community, P was associated with higher risks for severe NP and NP-induced CT interruption, compared to D. The findings are consistent with published trials and call for close observation of NP when using paclitaxel. Additional data from the community settings are needed to confirm these results. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis
Abstract 2755: Regulation of 53BP1 by the structural nuclear protein NuMA
Authors: Naike Salvador Moreno
Journal: Cancer Research (2016)

Abstract DNA double-strand breaks (DSBs) can cause genomic instability and cancer through point mutations and genomic translocations if they are not properly repaired. DSBs are repaired by two major pathways: homologous recombination (HR) or nonhomologous end joining (NHEJ). The cellular choice between these two pathways is critical to cell survival and is altered in cancers. 53BP1, which promotes NHEJ by blocking CtIP-dependent DNA resection, is a key protein mediating repair pathway choice. Here, we present a new negative regulation mechanism of 53BP1 that relies on the structural nuclear protein NuMA. Apart from its role in mitotic spindle assembly, NuMA influences chromatin organization during the interphase and modulates the chromatin response to DNA damage. We identified an interaction between NuMA and 53BP1 by proteomics analysis of a 53BP1 pull-down and confirmed this interaction by NuMA immunoprecipitation. We measured greater than 50% decreased 53BP1-NuMA binding in response to DSB, which suggest that, in the absence of DNA damage, NuMA may restrain 53BP1 diffusion. This hypothesis is supported by fluorescence correlation spectroscopy (FCS) measurements in cells expressing GFP-tagged 53BP1, as well as by microirradiation experiments in which NuMA overexpression or silencing inhibited or promoted 53BP1 recruitment at DNA damage sites, respectively. 53BP1 has an essential role in B cell class switch recombination (CSR) and mediates PARPi sensitivity in BRCA1-null cells. We will present how modulating NuMA expression affects both aspects of 53BP1 function. The results from our work will help to understand how 53BP1 is controlled, and shed light on the mechanisms regulating this modulator of PARPi sensitivity in the presence or absence of DNA damage. Citation Format: Naike Salvador Moreno. Regulation of 53BP1 by the structural nuclear protein NuMA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2755.