tbuckley/cabot-search huggingface dataset:
Abstract 811: VAL083, a novel N7 alkylating agent, surpasses temozolomide activity and inhibits cancer stem cells providing a new potential treatment option for glioblastoma multiforme
Authors: Kaiji Hu, Abbas Fotovati, James Chen, Joanna Triscott, Jeffery Bacha, Dennis Brown, Sandra E. Dunn
Journal: Cancer Research (2012)

Abstract Glioblastoma (GBM) remains one of the most difficult tumors to treat in part because many new agents fail to cross the blood brain barrier (BBB) and secondly due to intrinsic drug resistance. Temozolomide (TMZ) is a front-line therapy for the treatment of GBM, however, it is often ineffective due to drug inactivation by O6-methylguanine-DNA methyltransferase (MGMT). Cancer stem cells (CSC) are a subpopulation of the tumor that resist therapy and give rise to relapse. Here we described VAL083 a novel alkylating agent that creates N7 methylation on DNA, which was initially intriguing because it crosses the BBB. We addressed how it compared to TMZ, whether it could be used to overcome MGMT-driven drug resistance and if it has activity against CSCs. Addressing these questions provides further preclinical support for VAL083, which is currently undergoing human clinical trials in the USA against refractory GBM. VAL083 inhibited U251 and SF188 cell growth in monolayer and as neurospheres better then TMZ and caused apoptosis after 72 hrs. In a 10-day colony formation assay, VAL083 (5uM) suppressed SF188 growth by ∼95%. T98G cells are classically TMZ resistant and express MGMT yet VAL083 inhibited their growth in monolayer after 72 hrs in a dose-dependent manner (IC50&amp;lt;5 uM). VAL083 also inhibited the growth of CSCs by 100% in neurosphere growth assays. In summary, VAL083 has better in vitro efficacy than TMZ against brain tumor cells, can overcome resistance associated with MGMT, and targets brain tumor CSCs demonstrating that it has the potential to surpass the standard-of-care. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 811. doi:1538-7445.AM2012-811
Abstract 1660: Cholesterol efflux transporter gene expression predicts clinical outcome in serous ovarian cancer
Authors: Michelle J. Henderson, Ellen L. Hedditch, Amanda J. Russell, Anna deFazio, Catherine Emmanuel, Joshy George, Georgia Chenevix-Trench, David Bowtell, Murray D. Norris, Michelle Haber
Journal: Cancer Research (2011)

Abstract Ovarian cancer is a devastating disease. More than half the women diagnosed with advanced disease will die within five years. Tumours displaying serous histology are the most common, and although initially responsive to current chemotherapy regimens, the disease is characterised by a frequent rate of relapse, often with disease that is resistant to further treatment. Tumours displaying serous histology are the most common and often have the worst prognosis. The ATP-binding cassette (ABC) transporter superfamily consists of 48 functional transmembrane proteins which are further classified into seven subfamilies according to sequence similarity, designated A through G. Various members of the B, C and G branches are well-known for their abilities to convey drug resistance to cancer cells in vitro, but their precise roles in determining clinical outcome are still unclear. In addition, ABC transporters have important and diverse physiological roles through active transport of a variety of endogenous substrates, which could also contribute to tumour phenotype and treatment response. This is the first study to explore the entire ABC transporter gene family in relation to clinical outcome of ovarian cancer. Using a Taqman low density array format for real-time PCR, we examined expression of all ABC transporter genes in a cohort of 150 serous ovarian cancers. Kaplan-Meier survival analysis revealed that expression of multiple ABCA family transporters was significantly associated with progression-free or overall survival and multivariate modelling identified ABCA1, ABCA5, ABCA6, ABCA8 and ABCA9 as new prognostic markers for serous ovarian cancer that are independent of established clinical indicators. The prognostic significance of ABCA family transporter expression was validated in an independent microarray dataset consisting of 350 serous tumours available through The Cancer Genome Atlas. These ABCA family transporters are not known to transport drugs but instead function in cellular lipid trafficking and cholesterol homeostasis, suggesting that treatment failure may involve mechanisms other than simple efflux of chemotherapeutic drugs. In light of accumulating evidence for the importance of cholesterol and bioactive lipids in several cancers, this study highlights an important area for investigation into the biology and treatment of serous ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1660. doi:10.1158/1538-7445.AM2011-1660
Unexpected Findings on Gallium-67 Scintigraphy
Authors: Yu-Chin Wu, Te-Chun Hsieh, Shung-Shung Sun, Woei-Chung Lo, Tze-Yi Lin, Chun-Fan Yang, Kuo-Yang Yen, Chia-Hung Kao
Journal: Clinical Nuclear Medicine (2011)

We reported an extremely rare case of undifferentiated endometrial stromal sarcoma imaged with gallium-67 scintigraphy. This previously healthy 32-year-old woman presented with cough and dyspnea for days. Unexpectedly, the pathology of the opacity in the right pulmonary hilar region demonstrated metastatic high-grade epithelioid sarcoma. Gallium scintigraphy performed to detect possible origin showed abnormal uptake in the right supraclavicular region, chest region and pelvic region. Computed tomography-guided biopsy of the pelvic mass revealed undifferentiated endometrial stromal sarcoma. This case demonstrated the usefulness of gallium-67 scintigraphy in the detection of the primary disease and the evaluation of the metastatic disease.
FRI0226 Rituximab versus abatacept in rheumatoid arthritis patients with an inadequate response to prior biologic therapy: a retrospective single-center study
Authors: E. Keystone, D. Weber, J. Xiong, Y. Sun, A. Grant
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Patients with RA who experience an inadequate response to TNF inhibitor (TNFi) therapy (TNF-IR) may be successfully treated using an alternative TNFi or a biologic with a different mode of action such as rituximab (RTX) or abatacept (ABA). The relative effectiveness of these approaches has not been determined in head-to-head trials. Evidence from real-world experience would help to guide treatment decisions for TNF-IR patients. <h3>Objectives</h3> To evaluate the relative effectiveness of RTX and ABA in patients who failed at least one TNF inhibitor. <h3>Methods</h3> This was a retrospective chart review of patients from a single site (Rebecca MacDonald Center) with ACR-defined RA who initiated RTX or ABA after failure of at least one TNFi. The relative effectiveness of RTX and ABA was evaluated by analyzing drug survival distribution. Kaplan-Meier survival curves were compared using the log rank test (<i>p</i>-values &lt;0.05 indicated statistical significance). <h3>Results</h3> The study cohort comprised 61 patients, of whom 37 and 24 were treated with RTX and ABA, respectively. In the RTX group, 10 patients had also received prior therapy with ABA. Demographics and disease characteristics were generally similar in the two groups, although RTX patients had higher disease activity compared with ABA patients (mean CDAI: RTX 32.5 vs. ABA 26.9) and had received more prior TNFis (1.8 vs. 1.7) and/or ABA (2.1 vs. 1.7). After excluding the RTX patients who had received prior ABA, survival rates over time were generally better with RTX vs. ABA. Estimated survival rates at time 1.0, 2.0, 3.0 and 4.0 years were 0.79, 0.68, 0.68, and 0.68 for RTX and 0.74, 0.54, 0.54, and 0.41 for ABA. Overall, survival distribution was not significantly different between the RTX and ABA groups (<i>p</i>=0.658); however, RTX patients who had also failed ABA had significantly reduced survival compared with those who had not received ABA (<i>p</i>=0.015). Stratification of survival data according to number of prior TNFi failures indicated that RTX (exluding patients with prior ABA) was superior to ABA among patients who had failed 3 TNFis. Survival was also numerically greater with RTX vs. ABA in patients who had failed 1 prior TNFi. <h3>Conclusions</h3> These results from real-life practice suggest that in RA patients who failed one or more TNFi, RTX may have better long-term survival than either ABA or an alternative TNFi. Prior ABA appears to reduce RTX efficacy. Further data are needed. <b>Disclosure of Interest</b>: None Declared
Abstract 2151: Molecular screening of CRC from India suggests the existence of non-canonical pathway(s) of tumorigenesis
Authors: R Ratheesh, K Viswakalyan, A K. Chaudhary, G Swarnalata, M Srinivasulu, M Lavanya, V Anjayneyulu, S Patnaik, M Vamsy, S Murthy, K Ravikanth, R A. Sastry, M D. Bashyam
Journal: Cancer Research (2010)

Abstract A major risk factor for Colorectal Cancer (CRC) is advanced age, with a majority of cases reported in the West being above 60 years of age. However, a significantly high proportion of CRC patients from India belong to a younger age group (less than 50 years) and a majority of them have no family history of cancer. A deregulated Wnt signaling pathway is the hallmark of CRC in the West and has been indicted in 70-80% of older patients. Another significant genetic aberration is Microsatellite Instability (MSI), which may contribute to 15-20% of the cases. In addition, the simultaneous occurrence of Wnt activation and p53 inactivation has been substantiated in a significantly high proportion (about 70%) of CRC cases. Sporadic CRC occurring in the young however has not been subjected to detailed analysis so far. In order to identify important deregulated pathways that drive tumor progression in young patients we have initiated a multipronged comparative study on CRC occurring in the young and older patients from India. Our results have revealed several unique features among Indian CRC patients. Firstly, Wnt activation and p53 inactivation appeared to co-exist in a significantly less proportion of samples (34%), indicating existence of alternate pathway(s) of tumor initiation. Secondly, a significantly low proportion (35%) of young patients appeared to harbor a deregulated Wnt signaling pathway, when compared to older patients (64%). Thirdly, we did not find a significant difference in other variables between the two patient age groups including gender, grade, MSI status, etc. Using array-based Comparative Genomic Hybridization (aCGH) and genome-wide transcript profiling, we identified several copy number alterations (CNA) that may harbor genes important for tumor progression in young patients. A novel amplification located at 17q11.2-21.1 was identified which included genes involved in the MAP kinase pathway. The present study is expected to yield invaluable insights into the molecular basis for sporadic CRC in the young. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2151.
AB0633 Treating to target ultrasound findings only is equivalent to urate-lowering therapy in patients with chronic gout.
Authors: K. Kume, K. Amano, S. Yamada, T. Kanazawa, H. Ohta, K. Hatta, H. komori
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Urate-lowering therapy (uric acid&lt;6.0 mg/dL) (ULT) is recommended in chronic gout. In these days ultrasound (US) is very improved, and useful for diagnosis and treatment. <h3>Objectives</h3> To comparerecurrent gout attacks in chronic gout treated by US findings normalization strategy or ULT strategy. <h3>Methods</h3> We designed an open label, randomized controlled trial. We screened 74 chronic gout (uric acid&gt;7.0 mg /ld., and double contour sign of US findings in any joint) for inclusion. 63 gout patients were randomly allocated either US strategy group (US group) or ULT group(C group). In both strategies febuxostat is used. US strategy is performed US by 4 weeks. Double contour sign or urate crystals were evaluated; febuxostat is intensified to dissolve it. ULT strategy is performed blood examination by 4 weeks. Febuxostat is intensified to target uric acid &lt;6.0mg/dL. Primary outcome measure were proportion of no recurrent attack within 52 weeks. Analysis was by intention-to-treat. <h3>Results</h3> The characteristics of each group at baseline were not significantly different. There was no significant difference in the proportion of no recurrent attack within 52 weeks between the US strategy (87.6%) and ULT strategy (83.4%) groups. There was no significant difference in the occurrence of adverse events (AEs) between the US strategy and ULT strategy groups. <h3>Conclusions</h3> In chronic gout, if the patients were treated by febuxostat, US without blood examination might be equivalent to uric acid in blood. <h3>References</h3> A systematic review of <b>ultrasonography</b> in <b>gout</b> and asymptomatic hyperuricaemia. Chowalloor PV, et al. Ann Rheum Dis. 2013 Jan 3. [Epub ahead of print]2. EULAR evidence based recommendations for <b>gout</b>. Part II:Management. Report of a task force of the EULAR Standing Committee For International Clinical Studies Including Therapeutics (ESCISIT). Zhang W, et al. Ann Rheum Dis. 2006 Oct;65(10):1312-24. Epub 2006 May 17.3. Efficacy and Tolerability of <b>Febuxostat</b> in Hyperuricemic Patients With or Without <b>Gout</b>: A Systematic Review and Meta-Analysis. Ye P, et al. Clin Ther. 2013 Jan 15. doi:pii: S0149-2918(12)00723-0. 10.1016/j.clinthera.2012.12.011. <b>Disclosure of Interest</b>: None Declared
Renal Cell Carcinoma Presenting as Isolated Thyroid Metastasis 13 Years After Radical Nephrectomy, Detected on F-18 FDG PET/CT
Authors: Kuruva Manohar, Bhagwant Rai Mittal, Raghava Kashyap, Anish Bhattacharya, Baljinder Singh
Journal: Clinical Nuclear Medicine (2010)

We report a case of renal cell carcinoma presenting as isolated thyroid metastasis, 13 years after radical nephrectomy for the primary disease. F-18 FDG PET/CT provided valuable information regarding thyroid being the only site of metastatic involvement, which lead to further appropriate management.
Abstract 3759: P7170, a novel inhibitor of phosphoinositide 3-kinase (PI3K)-mammalian target of Rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) as a new therapeutic option for Kras mutated non small cell lung cancer (NSCLC)
Authors: Veena R. Agarwal, Asavari Joshi, Magesh Venkataraman, Dimple Bhatia, Julie Bose, Lakshmi Sireesha Kolla, Parkash Gill, Somesh Sharma
Journal: Cancer Research (2012)

Abstract Major breakthroughs in targeted cancer treatment have been achieved in last decade, but still some patient populations such as Kras mutated non small cell lung cancer (NSCLC), have no therapeutic options other than cytotoxic therapies. Therefore, development of targeted therapeutics is warranted in order to provide improved survival benefit for NSCLC patients with Kras mutation. P7170 is a small molecule inhibitor of PI3K (IC50 = 2.2 nM) and mTOR (IC50 = 4.4 nM). It also inhibits ALK1 and DNA-PK, two important enzymes involved in angiogenesis and DNA repair with IC50 of 47 and 1.5 nM, respectively. The structure, other in vitro, and in vivo efficacy of P7170 has been reported in the accompanying abstract submitted for AACR 2012. P7170 inhibited PI3K-mTOR pathway proteins pAKT, pS6 and p4EBP1 by 90 to 100 % in Kras mutated NSCLC cell line (H460) in a western blot assay. P7170 also exhibited potent cytotoxicity activity against two Kras mutated NSCLC (H460 and A549) cell lines with IC50 values of 7 and 5 nM. P7170 inhibited anchorage independent colony formation of tumor cells isolated from 10 different human tumor xenografts derived from NSCLC patient's tumors (Seven out of 10 samples had wild type Kras, and three had mutations in Kras). Moreover, P7170 induced apoptosis in H460 cell lines by inducing PARP cleavage. More interestingly, P7170 inhibited pAKT and pS6 in a dose dependent fashion in stem-like cells isolated from tumor samples of a Kras mutated NSCLC patient. P7170 demonstrated significant (p&amp;lt;0.01) in vivo efficacy following oral administration, in NSCLC xenograft studies using Kras mutated H460 cancer cell line. P7170 treatment resulted in 66% tumor growth inhibition at a dose of 5 mg/kg, and stabilization of tumor growth (89% tumor growth inhibition) at a dose of 20 mg/kg. Evaluation of mechanism of action of P7170 in H460 xenografted tumors confirmed the inhibition of PI3K-mTOR (pAKT and p4EBP) and Ras-Raf (pERK) pathways. In addition, inhibition of ALK1 and DNA-PK activity with the treatment of P7170 was also confirmed in xenografts. Conclusion: P7170 by virtue of its unique profile represents an opportunity to deliver a first-in-class therapeutic option for patients saddled with Kras mutated non small cell lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3759. doi:1538-7445.AM2012-3759
Abstract 4960: The role of YY1 in paclitaxel-induced cytotoxicity in epithelial ovarian cancer
Authors: Tsuyoshi Ota, Takayo Ota, Jeremy Chien, Viji Shridhar, Hirohisa Kurachi
Journal: Cancer Research (2012)

Abstract The Yin Yang 1 (YY1) transcription factor is a member of Polycomb protein family, with important roles in development, differentiation, replication and cell proliferation. While YY1 expression is correlated with survival in serous ovarian cancer, its role in chemotherapeutic agent-mediated cytotoxicity is not known. Immunoblot analysis revealed that YY1 is highly expressed in ovarian cancer cell lines, but not in immortalized ovarian surface epithelial (OSE) cell lines, suggesting a possible role of YY1 in ovarian carcinogenesis. shRNA mediated stable downregulation of YY1 resulted in inhibition of proliferation by CyQuant assay in SKOV3 and SKOV3ip cells. While YY1 downregulation increased the sensitivity against paclitaxel in both cell lines compared to nontargeted cells (NTC) as determined by MTT and clonogenic assays, it had no effect on sensitivity to cisplatin-mediated cytotoxicity. YY1 downregulated clones treated with paclitaxel resulted in an increase in cleavage of poly (ADP-ribose) polymerase and caspase-3/7 activity compared to NTC clones treated with it in SKOV3 and SKOV3ip1 cells. To determine the mechanism of paclitaxel sensitivity modulated by YY1, we performed cell cycle analysis and determined the expression of microtubules at protein level. Cell cycle analysis showed that downregulation of YY1 decreased the proportion of G0/G1 phase with corresponding increase in cells accumulating both S and G2/M phases in SKOV3 and SKOV3ip1 cells. Using nocodazole which synchronizes cells into mitotic phase, we found that blocking mitotic exit by YY1 knockdown slowed the cyclin B1 proteolysis, thus allowing more time for death initiation by paclitaxel. Immunoblot analysis showed that downregulation of YY1 increased the acetylation of alpha-tubulin and attenuated betaIII-tubulin expression compared to NTC cells. Immunoprecipitation and immunofluorescence assays revealed that YY1 interacts with HDAC6 which deacetylates alpha-tubulin and these proteins co-localized in mitotic phase, suggesting that dysfunction of HDAC6 by downregulation of YY1 could lead to microtubules stabilization, resulting in the paclitaxel-induced apoptosis by blocking mitotic exit. Moreover, nude mice bearing xenografts with stable downregulation of YY1 in SKOV3ip1 were more sensitive to paclitaxel-induced cytotoxicity compared to xenografts of NTC cells. Additionally immunohistchemical staining showed a decrease in betaIII-tubulin expression in tumor of YY1 downregulated clones compared to that of NTC clones. Collectively, these results indicate that YY1 acts as a modulator of microtubules expression and might be therapeutically targeted against epithelial ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4960. doi:1538-7445.AM2012-4960
FRI0091 Neutrophil CD64 (NCD64) as A Useful Marker for Differentiating Organizing Pneumonia (OP) from Bacterial Pneumonia (BP) in Rheumatoid Arthritis (RA):
Authors: S. Teshigawara, S. Tsuji, A. Kikuchi-Taura, A. Yura, M. Katayama, A. Watanabe, M. Yoshimura, E. Kudo-Tanaka, Y. Harada, Y. Katada, M. Matsushita, S. Ohshima, J. Hashimoto, Y. Saeki
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> In rheumatoid arthritis (RA), pulmonary involvement is one of the important complication.Both organizing pneumonia (OP) and bacterial pneumonia (BP) can be evident during the course of RA. However, we often have difficulties with differentiating OP from BP clinically, because both present similar infiltrations in chest computed tomography (CT). Corticosteroid is the standard therapy for OP, on the other hand, antibiotics is necessary for BP.CD64 on neutrophils (nCD64) is FcγRI known to be upregulated as a response to infection. <h3>Objectives</h3> To evaluate the usefulness of nCD64 for differentiating OP from BP. <h3>Methods</h3> Eleven RA patients diagnosed as pneumonia with infiltrative shadows in their chest CT were enrolled in this study. Five patients were successfully treated only with predonisolone (PSL). Three of them were pathologically confirmed the tissue of lung lesions by transbronchial lung biopsy (TBLB). They were diagnosed as OP. Nine patients were successfully treated with only broad-spectrum antibiotics (ABx), diagnosed as BP. All patients received blood examinations before treatment and following parameters were examined. The expression level of CD64 per neutrophil (nCD64) was quantitatively measured by using flow cytometery. C-reactive protein (CRP) and procalcitonin (PCT) were also measured. Comparisons of levels within each group were analyzed using the Mann-Whitney9s U-test. <h3>Results</h3> nCD64 levels in OP were significantly lower than those in BP (p=0.0164). On the other hand, in CRP and PCT, there were no differences between OP and BP. Among these biomarkers, only nCD64 can distinguish OP from BP, indicating the efficacy of nCD64 for diagnosis of OP. <h3>Conclusions</h3> nCD64 is an effective diagnostic marker for differentiating OP from BP in RA patients. This novel marker would be contribute to both early diagnosis and suitable treatment. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2901
Relation of Meat, Fat, and Fiber Intake to the Risk of Colon Cancer in a Prospective Study among Women
Authors: Walter C. Willett, Meir J. Stampfer, Graham A. Colditz, Bernard A. Rosner, Frank E. Speizer
Journal: New England Journal of Medicine (1990)

The rates of colon cancer in various countries are strongly correlated with the per capita consumption of red meat and animal fat and, to a lesser degree, inversely associated with the consumption of fiber.