tbuckley/cabot-search huggingface dataset:
Abstract 3778: In vitro and in vivo characterization of E7090, a novel and selective FGFR inhibitor, for the treatment of endometrial cancer
Authors: Saori Watanabe Miyano, Yuji Yamamoto, Kotaro Kodama, Naoko Hata Sugi, Yukinori Minoshima, Junji Matsui, Masao Iwata
Journal: Cancer Research (2016)

Abstract Genetic abnormalities (gene fusion, mutation and amplification) of Fibroblast Growth Factor Receptor (FGFR) family members are known to cause constitutive activation of their signaling pathways, which play an important role in proliferation, survival and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR2 is mutated in about 10% of endometrial cancer patients and is associated with a higher risk of recurrence. E7090, an oral available FGFR1, 2, and 3 inhibitor that the chemical-structure and basic kinase inhibitory activity of this compound have been presented at AACR2015, is currently under a first-in-human study (NCT02275910) in Japan. In this presentation, the efficacy of E7090 against human endometrial cancer was examined. E7090 exhibited selective potent antiproliferative activity against 3 human endometrial cancer cell lines harboring FGFR2 mutation with IC50 values of approximately 10 nM among 8 endometrial cancer cell lines. These cell lines harbor S252W mutation (extracellular domain mutation; MFE280) or N549K mutation (kinase domain mutation; AN3CA and MFE296), that are the most common mutations of FGFR2 in endometrial cancer. E7090 also showed antiproliferative activity against Ba/F3 cells expressing mutated type of FGFR2, confirming the inhibitory activity of E7090 against mutated FGFR2. The antiproliferative activity of E7090 against these cell lines was based on inhibition of phosphorylated FRS2α and ERK1/2 as downstream molecules of FGF/FGFR signaling. Especially, the antiproliferative activities of E7090 against AN3CA and MFE296 harboring N550K mutation were more potent compared to these of other FGFR specific inhibitors. In addition, oral administration of E7090 resulted in significant tumor growth inhibition in MFE280, AN3CA and MFE296 xenograft models in mice. Especially, E7090 showed tumor regression in AN3CA xenograft model with a delta T/C value of -66% at a dose of 50 mg/kg. These results indicated that E7090 showed potent inhibitory activity against mutated type of FGFR2 both in vitro and in vivo, and suggest that E7090 may provide therapeutic opportunities for endometrial cancer harboring FGFR2 mutations. Citation Format: Saori Watanabe Miyano, Yuji Yamamoto, Kotaro Kodama, Naoko Hata Sugi, Yukinori Minoshima, Junji Matsui, Masao Iwata. In vitro and in vivo characterization of E7090, a novel and selective FGFR inhibitor, for the treatment of endometrial cancer. [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 3778.
Abstract 2558: A retrospective analysis of the spectrum of genetic variations associated with hereditary cancers in Indians
Authors: Lakshmi Mahadevan, Aditya Nair, Vedam L. Ramprasad
Journal: Cancer Research (2016)

Abstract The hereditary cancer burden in India is on the rise due to an increase in awareness of the disease, decrease in the cost of genetic testing and opportunities for genetic counseling. More and more individuals from high risk families are undergoing genetic testing to assess their likelihood of developing the disease. On the other hand, the clinical community is facing a significant challenge on how to interpret and classify a variant as disease-causing or benign. This is because a large fraction of the variants identified in the affected individuals from India have not been reported in hereditary disease databases such as the Breast cancer Information Core (BIC), Clinvar and Swissvar. These variants of unknown significance (VUS) present in individuals from high risk families create a great deal of uncertainty on clinical follow up and disease management. We performed a retrospective analysis on more than 300 affected cases of hereditary ovarian and breast cancer tested at our genomics center in the last three years. We compiled all the known pathogenic variants and compared their distribution in the Indian cohort with what has been reported worldwide. The most prevalent mutation in BRCA1 p.Glu23Valfs*17 (185delAG) was detected at a frequency of 20.34% in line with what has been found worldwide. In addition, frameshift mutations in BRCA1 and BRCA2 were most frequently detected in breast and ovarian cancer in line with previous findings. Additionally, our analysis identified 13 novel previously unreported and potentially pathogenic variants in BRCA1 and BRCA2 genes. Variants were also detected in several moderate penetrance genes such as CHEK2, BARD1 and ATM involved in DNA damage response and in MSH2 and MSH6 genes regulating epigenetic control through chromatin modification. In this study, we report novel pathogenic variants in genes associated with hereditary breast and ovarian cancer in the Indian population. Citation Format: Lakshmi Mahadevan, Aditya Nair, Vedam L. Ramprasad. A retrospective analysis of the spectrum of genetic variations associated with hereditary cancers in Indians. [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 2558.
Abstract 4193: Reporter systems to measure dynamics and specificity of targeted cancer therapy
Authors: Rebecca T. Marquez, Liang Xu
Journal: Cancer Research (2016)

Abstract The Precision Medicine Initiative has driven the need for targeted therapy development to increase cancer patient survival. Due to this initiative, developing enhanced methods for measuring the accuracy and specificity of lead compound delivery is critical for moving these compounds through preclinical studies at a more efficient rate. The Experimental and Preclinical Imaging Core at the University of Kansas (epicore.ku.edu) is developing reporter constructs to assist in validating lead compound inhibition of oncogenic targets. Our lentiviral reporter constructs are used to establish stable cell lines that can be used either in vitro or in vivo to ensure optimal target inhibition. Our constructs include promoter reporters as well as 3’ untranslated-region (UTR) reporters to measure either changes in mRNA stabilization or translation by RNA-binding proteins or microRNA target validation. Our goal is to provide reporter constructs that will enable industry and academic institutions to ensure optimal inhibition of signaling pathways targeted by their lead compounds or microRNA-based therapies. Currently, we are constructing stable cancer cell lines that express near-infrared proteins, such as iRFP670, for measuring primary tumor and metastatic growth in vivo. In comparison to luciferase-expressing cell lines, we have found that cells expressing iRFP670 provided a more robust signal and were easier to image without the need for injecting a substrate. New promoter and 3’UTR reporters are being developed using iRFP670 and will be tested in vivo. Citation Format: Rebecca T. Marquez, Liang Xu, Experimental and Preclinical Imaging Core. Reporter systems to measure dynamics and specificity of targeted cancer therapy. [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 4193.
Abstract 4226: The rodent eye as a non-invasive window for understanding cancer nanotherapeutics
Authors: Xinlei Wang, Wenwu Xiao, Yuanpei Li, Pengfei Zhang, Mayank Goswami, Robert J. Zawadzki, Edward N. Pugh, Kit S. Lam
Journal: Cancer Research (2016)

Abstract We have successfully used the mouse eye as a non-surgical window for highly efficient, optical investigation of xenograft models, using a state-of-the-art ocular imaging facility, the UC Davis “EyePod”. The EyePod employs single-cell resolution intravital confocal microscopy and optical coherence tomography, performed completely non-invasively through the natural optics of the eye (1). This technology enables repeatable in vivo imaging over days, weeks and even months, quantitative tracking of tumor development and delivery of theranostic nanoparticles, and the measurement of tumor and tumor microenvironment responses. Moreover, the retina is a highly “approachable part of the brain”, so that non-invasive study of ocular tumors provides a platform for examining such critical issues as drug delivery across the blood retinal barrier (BRB) and blood brain barrier (BBB). Clinical metastasis of solid tumor to the uvea is not uncommon. Therefore, uvea/subretinal xenograft implant, even though not orthotopic, is clinically relevant. To visualize and photo-manipulate nanoparticle delivery to intraocular xenograft, we have used our recently reported nanoporphyrin (2) as the model system. This novel multifunctional porphyrin-based micellar nanoplatform allows (i) efficient encapsulation of hydrophobic chemotherapeutic drugs or fluorescent dyes, (ii) near-infra red fluorescent (NIRF) detection of the tumor via the intrinsic fluorescence of porphyrins, (iii) photodynamic therapy (PDT) and photothermal therapy (PTT) via efficient free radical and heat generation at the tumor site, respectively. Thorough understanding of how this nanocarrier distributes within the tumor microenvironment, and how it responds to controlled optical stimulation will enable us to maximize its therapeutic potential as a nano-theranostic agent. Preliminary FRET study with doxorubicin-loaded nanoporphyrin has allowed us to visualize in vivo and in real time the release of doxorubicin at the tumor site upon illumination with 680nm laser. In addition, the EyePod has enabled us to follow the tumor response over a period of 35 days. Work is currently underway to (i) develop patient-derived xenograft (PDX) model in the eye of NSG mice, and (ii) use EyePod to study the effect of tumor targeting and brain endothelial cell targeting peptides, recently developed in our laboratory, for nanodelivery into the tumor cells and across the BRB. Citation Format: Xinlei Wang, Wenwu Xiao, Yuanpei Li, Pengfei Zhang, Mayank Goswami, Robert J. Zawadzki, Edward N. Pugh, Kit S. Lam. The rodent eye as a non-invasive window for understanding cancer nanotherapeutics. [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 4226.
Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA.
Authors: Oliver A. Zill, Stefanie Mortimer, Kimberly C. Banks, Rebecca J Nagy, Darya Chudova, Coyt Jackson, Arthur Baca, Joseph Z. Ye, Richard Burnham Lanman, AmirAli Talasaz, Helmy Eltoukhy, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2016)

LBA11501 Background: Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) enables non-invasive profiling of solid tumor cancers. Liquid biopsy studies to date have been limited to modest-size cohorts and case studies. Methods: Somatic genomic profiles of over 15,000 patients with advanced-stage clinical cancer were determined by a highly accurate, deep-coverage (15,000x) ctDNA NGS test targeting 70 genes (Guardant360). Frequencies of somatic ctDNA alterations per gene were compared to those previously described in tissue sequencing projects (e.g., TCGA). Accuracy of ctDNA sequencing (PPV) was assessed by comparing with matched tissue tests for 386 patients. Results: The cohort consisted of lung (37%), breast (14%), colorectal (10%) and other cancers (38%), with ctDNA clinical sensitivity of 86%, 83%, 85%, and 78%, respectively. Cancer-type-specific frequencies and mutual exclusivity patterns among major driver alterations largely recapitulated those seen in tissue sequencing studies. Mutation frequencies per codon correlated well between ctDNA and published tissue data, both for commonly altered tumor suppressors and for oncogenes (Pearson correlations: TP53, r = 0.94; KRAS, r = 0.99; PIK3CA, r = 0.99). The overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87% (336/386). The accuracy increased to 98% when blood and tumor were collected less than six months apart. Four distinct classes of clinical outcome benefits have been observed by liquid biopsy: 1) actionable mutations in cases with tissue QNS ( ALK fusion, or EGFR or BRAF activating mutations in lung; ERBB2 amp in gastric), 2) actionable resistance mutations at time of progression ( MET amp or EGFR T790M in lung), 3) evolution of sensitivity upon progression ( ERBB2-amplified metastatic breast cancer with triple negative primary), 4) under-genotyped tumors ( BRAF V600E or ERBB2indel in lung). Conclusions: Somatic alteration patterns in ctDNA samples largely agree with tissue alteration patterns, with the exception of resistance mutations. Clinical outcome benefits have been observed for patients treated based on ctDNA findings.
Clinical and Immunological Activity of WT1 Peptide Vaccination in Patients with Acute Myeloid Leukemia and Myelodysplasia: Results of a Phase II Trial.
Authors: Ulrich Keilholz, Anne Letsch, Antonia Busse, Anne M. Asemissen, Alexander Schmittel, Wolf K. Hofmann, Lutz Uharek, Igor W. Blau, Eckhard Thiel, Carmen Scheibenbogen
Journal: Blood (2006)
Abstract 3597: RPS3 regulates melanoma growth and sensitivity to DNA damage and predicts a poor prognosis by targeting ADT3
Authors: Yun Tian, Lijun Qin, Wei Guo, Changlin Zhang, Dingbo Shi, Tianze Liu, Wenbing Li, Jingshu Wang, Yixin Li, Ge Qin, Wendan Yu, Xiangsheng Xiao, Tiebang Kang, Wenlin Huang, Wuguo Deng
Journal: Cancer Research (2016)

Abstract Melanoma, a malignant skin cancer, is resistant to DNA damage-mediated therapy. Discovering and identifying novel therapeutic targets for melanoma is urgently required. In this study, we found that ribosome protein S3 (RPS3) regulated melanoma growth and the sensitivity of melanoma to DNA damage by targeting ADP/ATP translocase 3 (ADT3). Knockdown of RPS3 inhibited cell proliferation and sensitized melanoma cells to DNA damage. RPS3 knockdown also promoted ADT3 translocation to mitochondrial of melanoma cells when exposed to DNA damage. RPS3 interacted with ADT3 in melanoma cells. Knockdown of ADT3 reduced its co-localization with RPS3. RPS3 could not obviously sensitize melanoma cells to DNA damage with ADT3 knockdown. In addition, we found that Lys18 in the death-induce-domain of RPS3 protein played a critical role in the interaction between RPS3 and ADT3. Mutation at Lys18 site could deadlock ADT3 and attenuate cell apoptosis in melanoma cells. Knockdown of RPS3 also inhibited tumor growth in a melanoma mouse model in vivo, but overexpression of the RPS3-18 mutation rescued the growth. Furthermore, we showed that the patients with higher expressed RPS3 had a much shorter median survival, whereas the patients with higher levels of ADT3 had a much longer median survival. Collectively, our results indicate that RPS3 cooperates with ADT3 to regulate the sensitivity of melanoma to DNA damage and suggest that the RPS3/ADT3 pathway is a potential therapeutic target for human melanoma. Grant support: This work was supported by the funds from the National Natural Science Foundation of China (81472178, 81272195) and the State “973 Program” of China (2014CB542005). Citation Format: Yun Tian, Lijun Qin, Wei Guo, Changlin Zhang, Dingbo Shi, Tianze Liu, Wenbing Li, Jingshu Wang, Yixin Li, Ge Qin, Wendan Yu, Xiangsheng Xiao, Tiebang Kang, Wenlin Huang, Wuguo Deng. RPS3 regulates melanoma growth and sensitivity to DNA damage and predicts a poor prognosis by targeting ADT3. [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 3597.
Abstract 1505: Radiogenomics defines key genomic network driving GBM invasion
Authors: Rivka R. Colen, Markus Luedi, Sanjay K. Singh, Islam Hassan, Joy Gumin, Erik P. Sulman, Frederick F. Lang, Pascal O. Zinn
Journal: Cancer Research (2016)

Abstract PURPOSE Clinical care and outcome in Glioblastoma (GBM) remains challenging due to the tumor's invasive grwoth. To establish personalized treatment options in GBM, discovery of genetic mechanisms essential for the tumor's invasion is needed. We have previously described radiogenomic approaches to diagnose gene networks non invasively by analyzing genomic data from TCGA. The purpose of the current reseach is to identify a genetic network that drives GBM invasion and can be targeted specifically. METHOD AND MATERIALS Using Kaplan-Meier statistics, the data of the two independent databases TCGA and REMBRANDT were used to validate the genetic netowork's impact on clinical outcome. The genes’ staus was assessed in a panel of human glioma stem cells (GSCs) and conventional proneural, classical and mesenchymal GBM cell lines using RT-PCR. Differentiation potential (Tuj1+ve, S100A+ve, and GFAP+ve), self-renewal (limiting dilution assays), invasion (Boyden chamber) and proliferation (BrdU) were assessed. Gain (lentiviral vectors) and loss (SMARTchoice Inducible shRNA) of function experiments were performed. Orthotopic xenograft models (nude mice) were used to characterize the genes impact in vivo. Potential FDA approved therapeutics were identified using connectivity map. RESULTS Texture analysis based on radiogenomics significantly predicted the genes responsible for invasion of GBM in a non-invasive manner. Invasion in both, in vitro and in vivo was significantly decreased upun downregulation of this gene network. Transcriptome micro-array analysis showed that an upregulation of the described genes results in class switching from proneural to mesenchymal sub-types. Cmap derived therapeutics could significantly inhibit the gene network's activitiy and hence invasion. CONCLUSION The describend genes could be essential drivers of molecular subtypes and invasion in GBM. The therapeutics defined with cmap offer a targetted therapy to adress these key features of GBM pathogenesis. Noninvasive radiogenomics-based identification of tumor subgroups and potential treatment approaches can significantly contribute to personalized therapy. CLINICAL RELEVANCE/APPLICATION The described gene network seems to be key for GBM pathogenesis. Noninvasive, radiogenomics-based subgroup identification and specific novel treatment approaches can significanty contribution to personalized GBM therapy. Citation Format: Rivka R. Colen, Markus Luedi, Sanjay K. Singh, Islam Hassan, Joy Gumin, Erik P. Sulman, Frederick F. Lang, Pascal O. Zinn. Radiogenomics defines key genomic network driving GBM invasion. [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 1505.
Human Coronavirus OC43 Associated with Fatal Encephalitis
Authors: Sofia Morfopoulou, Julianne R Brown, E Graham Davies, Glenn Anderson, Alex Virasami, Waseem Qasim, Wui K Chong, Michael Hubank, Vincent Plagnol, Marc Desforges, Thomas S Jacques, Pierre J Talbot, Judith Breuer
Journal: New England Journal of Medicine (2016)

In this case report, severe encephalitis with no established cause developed in a child with SCID. Through deep sequencing, human coronavirus OC43 was identified in brain tissue.
Protein Kinase C-Theta Interacts with mTORC2 and Vimentin to Limit Regulatory T-Cell Function
Authors: Cameron McDonald-Hyman, Govindarajan Thangavelu, James Muller, Guoan Zhang, Sudha Kumari, Asim Saha, Brent H. Koehn, Jason S. Mitchell, Brian T Fife, Jonathan S. Serody, Mark J. Osborn, Keli L. Hippen, Ameeta Kelekar, David H. Munn, Amnon Altman, Thomas A. Neubert, Michael L. Dustin, Bruce R. Blazar
Journal: Blood (2015)
Patterns of chemotherapy administration in bladder preservation therapy (BPT) for muscle-invasive bladder cancer (MIBC).
Authors: Tracy Lynn Rose, Sylvain Ladoire, Gilles Crehange, Matt D. Galsky, Jonathan E. Rosenberg, Joaquim Bellmunt, Thomas Powles, Yu-Ning Wong, Lauren Christine Harshman, Simon Chowdhury, Guenter Niegisch, Michael Liontos, Evan Y. Yu, Sumanta K. Pal, Ronald C. Chen, Andrew Wang, Matthew Edward Nielsen, Angela Smith, Matthew I. Milowsky
Journal: Journal of Clinical Oncology (2016)

4536 Background: Trimodality BPT in MIBC includes a maximal transurethral resection followed by concurrent chemoradiotherapy as an alternative to cystectomy in appropriately selected patients, or as a potential treatment in non-cystectomy candidates. Several chemotherapy regimens are used in BPT, but little is known about current practice patterns. This report describes chemotherapy utilization patterns and associated outcomes with BPT in MIBC. Methods: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3,024 consecutive patients from 29 international academic centers from 2005 to 2013. Patients with clinical T2-T4aN0M0 urothelial cancer of the bladder were included. Results: 269 patients received BPT. Compared with the 1,448 patients who received radical cystectomy, BPT patients were older (p = 0.01), less likely to have ECOG performance status of 0 or 1 (p < 0.01), and more likely to have clinical T4a disease (p < 0.01). 41% of BPT patients received concurrent chemotherapy with radiation. Patients receiving chemotherapy were younger (p = 0.01) and less likely to have T3 or T4 disease (p < 0.01) compared to patients who received radiotherapy alone. 25% of patients treated with chemotherapy received cisplatin only and 21% received carboplatin only. Additional regimens included gemcitabine alone (8%), paclitaxel (8%), 5-FU+mitomycin (5%), as well as others. Chemotherapy-treated patients had an adjusted HR for death of 0.89 (95% CI 0.61-1.29) compared to those who received radiotherapy alone after controlling for age, clinical T stage, and Charlson comorbidity index (median overall survival 26.5 vs 26.2 months, p = 0.37). There were no significant differences in survival among chemotherapy regimens. Only 10 patients (4%) eventually underwent cystectomy after BPT. Conclusions: A minority of patients undergoing BPT receive concurrent chemotherapy. The choice of chemotherapy used varies widely in clinical practice, with no clear standard. Salvage cystectomy is rarely performed. Continued research is needed on the comparative effectiveness among chemotherapy regimens in BPT.
Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage
Authors: Lindsay M. Kindinger, David A. MacIntyre, Yun S. Lee, Julian R. Marchesi, Ann Smith, Julie A. K. McDonald, Vasso Terzidou, Joanna R. Cook, Christoph Lees, Fidan Israfil-Bayli, Yazmin Faiza, Philip Toozs-Hobson, Mark Slack, Stefano Cacciatore, Elaine Holmes, Jeremy K. Nicholson, T. G. Teoh, Phillip R. Bennett
Journal: Science Translational Medicine (2016)

Cervical cerclage using braided suture material disrupts vaginal microbial stability and increases inflammation.