tbuckley/cabot-search huggingface dataset:
Abstract 1174: CT179 degrades the olig2 transcription factor in glioblastoma stem-like cells and prolongs survival
Authors: Gordon R. Alton, Graham Beaton, Susan Knowles, Gregory Stein, Santosh Kesari
Journal: Cancer Research (2017)

Abstract Olig2 is a bHLH transcription factor that has been shown to be a key driver of glioblastoma (GBM) tumorigenesis. Olig2 is expressed in human tumor-derived glioma stem-like cells. A growing body of evidence suggests that glioma stem-like cells (GSCs) are more representative of their parent tumors when cultured under defined serum-free conditions with the mitogens epidermal growth factor (EGF) and fibroblast growth factor (FGF). Furthermore, recent research has indicated that human Proneural GSCs grown in vitro in PDGF are more tumorigenic in vivo. We have designed and synthesized a potent inhibitor of Olig2 that possesses all the necessary properties for clinical development as an important new GBM therapeutic. CT179 dose dependently causes the degradation of Olig2 in multiple GBM cell lines and this correlates to G2/M arrest and increased apoptosis. CT179 also induces the loss of expression of EGFR and PDGFR in human GSCs. CT179 achieves high concentrations in the CNS with a long duration of pharmacologic action. Furthermore, CT179 significantly extends survival of mice implanted orthotopically with patient-derived human tumor GSCs. Immunohistochemistry demonstrates a marked reduction of Olig2 positive cells in the tumor bearing animals. Together, these results indicate that CT179 has significant promise as a new therapeutic for the treatment of human GBM. Citation Format: Gordon R. Alton, Graham Beaton, Susan Knowles, Gregory Stein, Santosh Kesari. CT179 degrades the olig2 transcription factor in glioblastoma stem-like cells and prolongs survival [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 1174. doi:10.1158/1538-7445.AM2017-1174
Abstract 950: Involvement of proinflammatory chemokine network between adipocytes and triple negative breast cancer cells
Authors: Rosa Mistica Coles Ignacio, Hyeongjwa Choi, Carla Gibbs, Eunsook Lee, Samuel Adunyah, Deok-Soo Son
Journal: Cancer Research (2017)

Abstract Obesity has become a global epidemic and causes a chronic low-grade inflammation. This poses a large health burden because excess adiposity can lead to chronic diseases such as type 2 diabetes, cardiovascular disease and some cancers. Obese individuals get higher incidence, progression and mortality of cancers compared to lean ones. Particularly, breast cancer (BC) in women is closely associated with obesity. Despite an epidemiological link between obesity and low cancer survival rates, little is known about the molecular mechanisms by which obesity promotes BC progression. Obesity-derived chronic low-grade inflammation involves alteration of a chemokine network that may contribute to the cancer progression and metastasis. Herein, we proposed the novel concept that the chemokine network between obesity and BC builds an inflammatory burden via proinflammatory chemokines to promote cancer progression. We employed mesenchymal BC cell PY8119 and epithelial-like BC PY230 for triple negative BC (TNBC) cell model, and mouse 3T3-L1 preadipocyte and adipocyte conditioned media (CM) to mimic lean and obese conditions in vitro. We examined the profiles of chemokine signature of PY8119 and PY230 treated with preadipocytes and adipocytes CM using PCR array. Both preadipocytes and adipocytes CM-treated PY8119 and PY230 cells absent or low levels in chemokine receptors. On the other hand, the chemokines CCL2, 5, 7 and CXCL10 showed higher expression in both preadipocyte and adipocyte CM-treated PY8119. Interestingly, adipocyte CM-treated PY8119 cells dominantly expressed CXCL1-3 compared to preadipocyte CM-treated cells. In addition, CCL2, 5, 7, 20, and CXCL1, 5, 10 were highly expressed in both preadipocyte and adipocyte CM-treated PY230 cells. Moreover, CXCL2 and 3 were significantly induced in PY230 cells after treatment with adipocyte CM compared to preadipocyte CM. Taken together, the results indicate that dominant chemokines CXCL1-3 expressed in adipocyte CM-treated TNBC cells promote a pro-tumor inflammatory network. Hence, these proinflammatory microenvironment augmented by adipocytes might contribute to TNBC progression. Citation Format: Rosa Mistica Coles Ignacio, Hyeongjwa Choi, Carla Gibbs, Eunsook Lee, Samuel Adunyah, Deok-Soo Son. Involvement of proinflammatory chemokine network between adipocytes and triple negative 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 950. doi:10.1158/1538-7445.AM2017-950
Abstract 4729: Association of mitochondrial DNA copy number variation in peripheral blood leucocytes with risk and prognosis of gallbladder cancer
Authors: Abhijit Chandra, Hasan R. Kazmi, Leena K. Satyam, Saket Kumar
Journal: Cancer Research (2017)

Abstract Gallbladder Cancer (GBC) is the most common malignancy of the biliary tract with very high incidence in Northern India, especially around Gangetic belt. Late diagnosis and poor prognosis are the important features of this disease. For improving treatment strategies and outcomes, novel non invasive prognostic biomarkers are needed. Variations in peripheral blood mitochondrial DNA (mtDNA) copy number in various cancers are widely studied but information in relation to gallbladder malignancy is unknown. In this pilot study, we investigated leucocytes mtDNA copy number variation in relation to risk and prognosis of GBC. A total of 300 histologically confirmed or fine needle aspiration cytology proven GBC patients were recruited along with equal number of age and sex matched controls. The mtDNA copy number was measured by real-time polymerase chain reaction through absolute quantification using SYBR green chemistry. We also explore prognostic utility of mtDNA content in relation to overall survival of GBC patients. Statistical analysis was done by Student’s test and survival data was compared using Kaplan Meier method. Two tailed p value less than 0.05 was considered to be significant. We observed high mtDNA content in cases as compared with controls (mean±standard deviation, 1.21±0.88 vs. 1.02±0.76). Higher mtDNA copy number was significantly associated with increased gallbladder cancer risk (p=0.005). In this study, we compared overall survival (OS) for gallbladder cancer patients in relation to mtDNA copy number median value (median, 1.12). Kaplan Meir survival curve predicts decrease in OS (p=0.03, Hazard ratio=2.54; 95% CI = 1.79-5.86) for GBC patients in relation to high mtDNA content (&amp;gt;median) as compared with low mtDNA copy number (&amp;lt;median). This study supports an association between increased mtDNA copy number with susceptibility to gallbladder cancer in this endemic belt. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in relation to gallbladder cancer. Citation Format: Abhijit Chandra, Hasan R. Kazmi, Leena K. Satyam, Saket Kumar. Association of mitochondrial DNA copy number variation in peripheral blood leucocytes with risk and prognosis of gallbladder 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 4729. doi:10.1158/1538-7445.AM2017-4729
Abstract 505: Somatic and inherited riboSnitches inTPT1andLCP1mRNA secondary structures
Authors: Lela L. Lackey, Aaztli Coria, Chanin Tolson, Evonne McArthur, Alain Laederach
Journal: Cancer Research (2017)

Abstract RiboSnitches are single nucleotide variants that change the secondary structures of RNA. These structural changes can have a regulatory or functional impact on the RNA. Many inherited single nucleotide variants function as riboSNitches. We wanted to investigate the potential of somatic mutations to act as riboSNitches. We determined the secondary structure of two cancer-associated mRNAs, TPT1 and LCP1, using the chemical probing SHAPE-Map technique. Both of these mRNAs are highly structured and have similar folds in vivo and in vitro. We analyzed the structural impact of all the synonymous somatic mutations identified in the COSMIC cancer sequencing database for both TPT1 and LCP1 mRNAs. In TPT1 we also tested several inherited variants. We found that both somatic and inherited variants can be riboSNitches, at approximately the same ratio. Our results are in accord with previous work indicating that ~15% of SNVs are capable of acting as riboSNitches. Although the impact of non-coding and synonymous somatic mutations are difficult to measure, it is becoming clear that these mutations can contribute to cancer progression and phenotype. The majority of our identified riboSNitches are detrimental according to FATHMM-MKL functional impact prediction. Our experiments indicate that a substantial fraction of somatic mutations can cause a measurable change to RNA structure, potentially changing the regulatory or functional behavior of that mRNA. Citation Format: Lela L. Lackey, Aaztli Coria, Chanin Tolson, Evonne McArthur, Alain Laederach. Somatic and inherited riboSnitches in TPT1 and LCP1 mRNA secondary structures [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 505. doi:10.1158/1538-7445.AM2017-505
Abstract 2149: Unusual expression of HPRT on the surface of the colorectal cancer cell lines HT29 and SW620
Authors: Evita G. Weagel, Michelle H. Townsend, Michael D. Anderson, Edwin J. Velazquez, K Scott Weber, Richard A. Robison, Kim L. O'Neill
Journal: Cancer Research (2017)

Abstract Colorectal cancer is one of the most common cancers in the world, affecting nearly 1.2 million people in the United States alone. The aim of this study is to investigate the salvage pathway enzyme HPRT as a possible biomarker in two colorectal cancer cell lines: HT29 and SW620. HPRT is a transferase in the purine salvage pathway that functions primarily by catalyzing the conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. Because of its role in proliferation and cell cycle regulation, we hypothesized an increase in HPRT expression within cancer cells, which could potentially lead to presentation on the surface of the cell. HPRT surface localization was assessed utilizing confocal microscopy, flow cytometry, and scanning electron microscopy. These techniques allowed us to visualize HPRT on the plasma membrane and quantify expression. There was statistically significant expression of HPRT on the surface of both HT29 and SW620 cells with a 28% and 58% fluorescent shift in the population, respectively. Confocal microscopy images revealed overlap between cells stained with a membrane dye and anti-HPRT FITC antibody, which indicates a direct relationship between HPRT and the plasma membrane of SW620 cells. To visualize the location of HPRT on the plasma membrane, anti-HPRT antibodies were labelled with gold and protein presence was quantified using an electron microscope, which measured the gold elemental weight percentage of each sample. When exposed to anti-HPRT antibody, the gold weight percentage of the samples significantly increased with 12.4% gold in SW620 cells and 11.2% gold in HT29 cells, indicating significant HPRT surface presence. The observed localization of HPRT to the plasma membrane was variable between the two different cancer cell lines. SW620 cells, which are faster growing and more aggressive, had significantly higher HPRT presentation that HT29 cells. These data collectively suggest that HPRT may be a possible biomarker target for the identification and possible treatment of colorectal cancer cells. Citation Format: Evita G. Weagel, Michelle H. Townsend, Michael D. Anderson, Edwin J. Velazquez, K Scott Weber, Richard A. Robison, Kim L. O'Neill. Unusual expression of HPRT on the surface of the colorectal cancer cell lines HT29 and SW620 [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 2149. doi:10.1158/1538-7445.AM2017-2149
Highly active antiretroviral therapy
Authors: Peter Mugyenyi
Journal: BMJ (2004)

The barriers to providing highly active antiretroviral therapy (HAART) in poor countries have until recently seemed insurmountable. The cited problems have ranged from weak health systems and poor infrastructure to inadequate numbers of health professionals. In reality, the main barrier has been the very high cost of antiretroviral drugs. Current increase in access to HAART has resulted from cuts in the price of antiretroviral drugs and increased funding by international bodies, notably the Global AIDS Fund, the World Bank, and the President Bush Emergency Program for AIDS Relief.

Africa's grim AIDS data include 25 million people living with HIV and 2.2 million dead in 2003 alone.1 The challenge now is to move quickly from small town or community specific projects to provide nationwide high quality, equitable, and sustainable programmes. Valuable lessons have been learned from pilot programmes in poor countries, including the Malawi experience described in this issue, but individually these do not provide a blueprint for universally applicable scale-up models (p 1163).2 However, if the cumulative knowledge from these programmes is applied with tactical adjustment tailored to the local conditions it should be sufficient for programmes to proceed, without the need for new pilot studies, which would be unethical if they deny or delay the provision of life saving treatment to patients.

The dreaded risk associated with scaling up HAART is the development of widespread drug resistance secondary to drug misuse,3 which in the long term may render the cheap first line antiretroviral drugs ineffective. Although initial data indicate good adherence4 and treatment outcomes in Africa, it is critical to enforce and maintain strong adherence strategies, as it is the key to success in controlling the carnage caused by HIV/AIDS.
Periodontitis epidemiology: is periodontitis under‐recognized, over‐diagnosed, or both?
Authors: Panos N. Papapanou, Cristiano Susin
Journal: Periodontology 2000 (2017)

Abstract Currently, two principal forms of destructive periodontal disease are recognized – chronic periodontitis and aggressive periodontitis – but their distinction in epidemiologic studies has been rather problematic because of substantial overlap of their primary features. This review critically appraises some key features relevant to the epidemiology of human periodontitis that underlie its core ‘identity’ as a bacterial biofilm‐induced, inflammatory disease and discusses its impact within the larger context of aging populations. The currently adopted epidemiologic methodologies/definitions that result in the almost ubiquitous prevalence of periodontitis indeed overestimate the occurrence of the disease that may actually put individuals at a true biologic, functional or psychosocial disadvantage. Use of these definitions has inevitably promoted the inference that periodontitis constitutes an insurmountable oral health problem. In contrast, reliance solely on physical measurements of probing depth and/or attachment loss under‐recognizes the true impact that periodontitis may have on the well‐being of individuals. It is currently unclear whether inclusion of the psychosocial and systemic dimensions of the disease in case definitions would result in higher or lower prevalence estimates. The review concludes that periodontitis should no longer be defined solely by gingival/periodontal inflammation in the presence of increased probing depths and attachment loss but should incorporate additional dimensions capturing impaired function, esthetics, and impact on general health and quality of life. A multidimensional approach to the assessment of periodontitis would facilitate an improved understanding of its epidemiology and consequences.
Abstract 3380: Synthetic lethal interaction between <i>ARID1A</i> mutation and BET bromodomain inhibition in ovarian clear cell carcinoma
Authors: Katrien Berns, Joseph J. Caumanns, E Marielle Hijmans, Annemiek Gennissen, Bastiaan Evers, Bea A. Wisman, Gert Jan Meersema, Cor Lieftink, Roderick L. Beijersbergen, Hiroaki Itamochi, Ate G. van der Zee, Steven de Jong, René Bernards
Journal: Cancer Research (2017)

Abstract Introduction: Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Given that ARID1A is inactivated by mutation in over 50% of ovarian clear cell carcinomas, we pursued an ARID1A synthetic lethal screening strategy to identify druggable targets in OCCC. Experimental procedures: We performed synthetic lethal kinome short hairpin (shRNA) screens in a large panel (n=14) of OCCC cell lines having different ARID1A mutation status. Hit validation was performed with isogenic ARID1A ko cell line pairs and in (patient-derived) xenograft mouse models. Summary of the data: We show here that BRD2 inhibition is synthetic lethal with ARID1A mutation in ovarian clear cell cancer cells. Importantly, inhibiting the BET family of proteins, to which BRD2 belongs, with small molecules specifically inhibits proliferation of ARID1A mutated cell lines both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. We demonstrate that ARID1A loss leads to upregulation of the WNT ligand WNT10B, possibly causing a WNT dependency in the ARID1A mutant lines. BET inhibitors cause a reduction in WNT10B expression and WNT target genes such as MYC, JUN and WISP1, providing a potential explanation for the observed synthetic lethal interaction with ARID1A loss. Conclusions: Our study uncovered a new synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition, suggesting a new treatment strategy for ARID1A mutant ovarian clear cell carcinomas. Citation Format: Katrien Berns, Joseph J. Caumanns, E Marielle Hijmans, Annemiek Gennissen, Bastiaan Evers, Bea A. Wisman, Gert Jan Meersema, Cor Lieftink, Roderick L. Beijersbergen, Hiroaki Itamochi, Ate G. van der Zee, Steven de Jong, René Bernards. Synthetic lethal interaction between ARID1A mutation and BET bromodomain inhibition in ovarian clear 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 3380. doi:10.1158/1538-7445.AM2017-3380
Silencing of the NF-kB p65 subunit inhibits HIF1-alpha expression during hypoxia and sensitizes HCT116 colon cancer cells to CPT11 but not TRAIL
Authors: Ogi Kazuhiro, Wafik El-Deiry
Journal: Cancer Research (2007)

1598   While investigating sensitivity of hypoxic cells to various therapeutic agents we observed that HIF1-alpha mRNA expression is increased during hypoxia. We hypothesized that NF-kB may transcriptionally upregulate HIF1-alpha during hypoxia. We performed ChIP assays and found that hypoxia induces recruitment of NF-kB p65 to the HIF1-alpha promoter. Following exposure to hypoxia, there was increased p65 localization in the nucleus. Using real-time PCR we found that Jurkat mutant IkB-expressing cells that overexpress p65 in the cytoplasm have decreased levels of HIF1-alpha as compared to wild-type Jurkat cells, either during normoxia or hypoxia. We tested the influence of p65 knockdown on cell survival after treatment of wild-type p53-expressing or p53-null HCT116 colon cancer cells by CPT11 or TRAIL and exposure to hypoxia. While both p53+/+ and p53-/- HCT116 cells showed sensitivity to TRAIL, the cells were relatively resistant to CPT11 under normoxic conditions. Under hypoxia, as we previously observed (Mayes et al., Cancer Biology and Therapy 4:1068-1074, 2005), p53-null HCT116 (and not p53+/+ cells) exhibit greatly reduced TRAIL-induced apoptosis. p65 knockdown did not enhance TRAIL sensitivity under normoxic or hypoxic conditions. Strikingly, inhibition of p65 in CPT11-resistant p53+/+ HCT116 cells significantly increased their sensitivity to CPT11 during hypoxia. This effect was diminished in p53-null HCT116 cells. Our results indicate that wild-type p53-expressing HCT116 cells are resistant to CPT11 in normoxia as well as hypoxia and that p65 knockdown results in increased CPT11-sensitivity in hypoxic HCT116 cells. From these findings we postulate that one of the mechanisms by which hypoxic p53-wild-type HCT116 cells become resistant to CPT11 may involve the expression of HIF1-alpha via transcriptional upregulation by NF-kB, and that this may lead to chemoresistance to CPT11. Further studies are ongoing to establish the potentially important role of NF-kB-mediated regulation of HIF1-alpha in CPT11-resistance under hypoxia.