tbuckley/cabot-search huggingface dataset:
Abstract 2264: Tumor fragmentation is a poor prognostic histologic biomarker for lung squamous cell carcinoma
Authors: Ruben Casanova, Alex Soltermann
Journal: Cancer Research (2016)

Abstract Introduction: Lung squamous cell carcinoma (SCC) is the second most frequent histologic type of non-small cell lung carcinoma (NSCLC). Next to pTNM staging, grading is also important for histomorphologic classification of tumors into relevant prognostic groups. SCC forms cohesive tumor sheets of various sizes, ranging from large pushing boundaries to small detached clusters. The presence of small clusters such as single cells, tumor buds 15 cells) could also contain prognostic information and hence be pertinent for tumor grading. Herein we propose a computer-based morphometric analysis for the global assessment of lung SCC fragmentation. Methods: Surgically resected lung SCC tumors (discovery tissue microarray cohort n = 208, 2 cores per patient; validation whole section cohort n = 99, 2 blocks per patient) were immuno-histochemically stained with pan-cytokeratin. Color-based segmentation (tumor epithelia brown, stroma blue-grey) allowed to separate tumor from stroma and to compute the number of tumor fragments. Associations with disease-free (DFS) and overall survival (OS) were assessed by univariate Cox regressions. Results: Tumor fragments were defined as tumor clusters &amp;gt;3000μm2 (circa &amp;gt;15 cells) entirely surrounded by stroma. Criteria for high fragmentation were: &amp;gt; 5 fragments summed over 2 TMA cores (range: 2-18, median = 5) and &amp;gt; 700 fragments summed over 2 whole sections (range: 94-3988, median = 570). Respectively, 44% and 42% of the patients had highly fragmenting tumors in the discovery (D) and validation cohort (V), correlating with blood vessel infiltration (cc = 0.181, p&amp;lt;0.001 (D); cc = 0.220, p = 0.029 (V)). High fragmentation was also associated with decreased OS (HR = 1.77, p = 0.001) and DFS (HR = 1.83, p = 0.027) in (D). This was confirmed in (V): OS (HR = 2.09, p = 0.004), DFS (HR = 2.60, p = 0.005). Conclusions: We used an automated morphometric approach for unbiased scoring of tumor fragmentation on digitalized histological sections. This versatile method could potentially be applied to virtually any solid human carcinoma. Our analysis revealed that tumor fragmentation is a poor prognosticator for lung squamous cell carcinoma, e.g. due to increased likelihood of vessel infiltration. Citation Format: Ruben Casanova, Alex Soltermann. Tumor fragmentation is a poor prognostic histologic biomarker for lung squamous cell 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 2264.
Monogenic and polygenic determinants of sarcoma risk: an international genetic study
Authors: Mandy L Ballinger, David L Goode, Isabelle Ray-Coquard, Paul A James, Gillian Mitchell, Eveline Niedermayr, Ajay Puri, Joshua D Schiffman, Gillian S Dite, Arcadi Cipponi, Robert G Maki, Andrew S Brohl, Ola Myklebost, Eva W Stratford, Susanne Lorenz, Sung-Min Ahn, Jin-Hee Ahn, Jeong Eun Kim, Sue Shanley, Victoria Beshay, Robert Lor Randall, Ian Judson, Beatrice Seddon, Ian G Campbell, Mary-Anne Young, Rajiv Sarin, Jean-Yves Blay, Seán I O'Donoghue, David M Thomas
Journal: The Lancet Oncology (2016)
A Prognostic System Predictive of Outcomes in Persons Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome
Authors: Brian C Shaffer, Kwang Woo Ahn, Zhen-Huan Hu, Uday R. Popat, Matt Kalaycio, Richard T. Maziarz, Edwin Alyea, Ron M Sobecks, Steven Z. Pavletic, Martin S Tallman, Wael Saber
Journal: Blood (2015)
Abstract LB-090: Sequence-based discovery of fully human anti-CD3 and anti-PDL1 single domain antibodies using novel transgenic rats
Authors: Nathan Trinklein, Shelley Force Aldred, Ute Schellenberger, Kat Harris, Starlynn Clarke, Kevin Dang, Duy Pham, Marianne Bruggemann, Wim vanSchooten.
Journal: Cancer Research (2016)

Abstract We have created a new platform and method for discovering fully human single domain antibodies (UniDabs) by combining novel transgenic rats (UniRats), antibody repertoire sequencing, and high-throughput gene assembly, expression and screening. UniRats express a comprehensive human VH gene repertoire in a heavy chain only antibody format, and they mount robust immune responses to a variety of antigens. UniRats do not produce endogenous Ig as their heavy, kappa and lambda loci have been silenced, so the only Ig expression comes from the human heavy chain transgenes. Human VHs identified using high-throughput functional screening of heavy chain antibodies may also be converted to a single domain UniDab format. UniDabs are powerful and flexible modular binding domains that may be combined to form multivalent structures, nanoparticle conjugates, or antibody-drug conjugates. In our preclinical CD3 and PDL1 programs, we have identified hundreds of antigen-specific UniDabs. This large collection of UniDabs covers a diverse set of epitopes, a wide range of affinities, and is a valuable resource for creating next-generation multi-specific cancer therapeutics. Citation Format: Nathan Trinklein, Shelley Force Aldred, Ute Schellenberger, Kat Harris, Starlynn Clarke, Kevin Dang, Duy Pham, Marianne Bruggemann, Wim vanSchooten. Sequence-based discovery of fully human anti-CD3 and anti-PDL1 single domain antibodies using novel transgenic rats. [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 LB-090.
2,3-Diaryl-3 H -imidazo[4,5- b ]pyridine derivatives as potential anticancer and anti-inflammatory agents
Authors: Erin Marie Kirwen, Tarun Batra, Chandrabose Karthikeyan, Girdhar Singh Deora, Vandana Rathore, Chaitanya Mulakayala, Naveen Mulakayala, Amy Catherine Nusbaum, Joel Chen, Haneen Amawi, Kyle McIntosh, None Sahabjada, Neelam Shivnath, Deepak Chowarsia, Nisha Sharma, Md Arshad, Piyush Trivedi, Amit K. Tiwari
Journal: Acta Pharmaceutica Sinica B (2016)

In this study we examined the suitability of the 3H-imidazo[4,5-b]pyridine ring system in developing novel anticancer and anti-inflammatory agents incorporating a diaryl pharmacophore. Eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives retrieved from our in-house database were evaluated for their cytotoxic activity against nine cancer cell lines. The results indicated that the compounds showed moderate cytotoxic activity against MCF-7, MDA-MB-468, K562 and SaOS2 cells, with K562 being the most sensitive among the four cancer cell lines. The eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives were also evaluated for their COX-1 and COX-2 inhibitory activity in vitro. The results showed that compound 3f exhibited 2-fold selectivity with IC50 values of 9.2 and 21.8 µmol/L against COX-2 and COX-1, respectively. Molecular docking studies on the most active compound 3f revealed a binding mode similar to that of celecoxib in the active site of the COX-2 enzyme.
Abstract 3485: Estrogen receptor ligands and their responses in de novo and tamoxifen resistant cell models
Authors: Lauren M. Gutgesell, Gregory R. J. Thatcher, Hitisha Patel, Rui Xiong
Journal: Cancer Research (2016)

Abstract Approximately 75% of breast cancer incidences are Estrogen Receptor positive (ER+). Tamoxifen, a selective estrogen receptor modulator (SERM), is the standard of care for many of these ER+ breast cancer patients. Unfortunately, tamoxifen resistance occurs in almost 50% of patients within 5 years of treatment, and endocrine-independence accompanying resistance negates the effects of aromatase inhibitors. Paradoxically, estradiol (E2) has shown clinical efficacy in patients with resistant breast cancer. Understanding the antiproliferative role of E2 and ER signaling in resistant ER+ cell lines is essential to gain a better understanding of paradoxical clinical efficacy and for the appropriate biomarker-assisted selection of endocrine therapy for various stages of ER+ breast cancer. We have discovered ER ligands, based upon a single chemical scaffold with a diverse set of pharmacological responses, which can be used to better understand the role of ER signaling in resistance and therapy: selective ER modulators (SERMs), selective ER downregulators (SERDs), selective estrogen mimics (SEMs), and selective human ER partial agonists (ShERPAs). These compounds were initially classified using an ERE luciferase reporter assay and affinity for ER confirmed by biochemical assays. The effects of these novel ER-directed chemical probes on cell viability were further examined in multiple 2D and 3D spheroid models of tamoxifen resistance. Finally, ERα localization upon administration of these ligands in tamoxifen-sensitive and tamoxifen-resistant cells was studied. While SERDs and SEMs showed growth inhibition in tamoxifen resistant cell lines, both molecules had different responses and mechanisms of growth inhibition. ERα was localized to extranuclear sites upon administration of E2, SEMs, and ShERPAs, an observation specific to the resistant phenotype and mechanistically associated with spheroid disintegration. SERDs inhibited the antiproliferative actions of E2, but were antiproliferative in resistant cell lines. Further dissection of the role of ER in resistance and survival is needed to define the appropriate ER-directed, endocrine therapy in ER+ breast cancer. Citation Format: Lauren M. Gutgesell, Gregory R. J. Thatcher, Hitisha Patel, Rui Xiong. Estrogen receptor ligands and their responses in de novo and tamoxifen resistant cell models. [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 3485.
Abstract 1861: The role and regulation of MTA1-ETS2 axis in prostate cancer
Authors: Avinash Kumar, Swati Dhar, Nasir Butt, Agnes Rimando, Luis Martinez, Anait Levenson
Journal: Cancer Research (2016)

Abstract Overexpression of the chromatin modifier protein, metastasis associated 1 (MTA1) in prostate cancer contributes to tumor aggressiveness, but the molecular mechanism involved has not been fully elucidated. MTA1 ChIP-Seq analysis in prostate tissues from the prostate-specific Pten heterozygous mice, which exhibit elevated levels of MTA1 revealed MTA1 recruitment onto the ETS2 promoter. Loss of function studies with MTA1 in various prostate cancer cell lines exhibited reduced expression for ETS2 at both mRNA and protein levels. We also observed increased expression of ETS2 at both mRNA and protein levels in prostate tissues from the prostate-specific MTA1 transgenic mice. Meta-analysis of prostate cancer samples in the GEO database exhibited a positive correlation between MTA1 and ETS2 levels. These results suggested that MTA1 functions as a coactivator for regulating ETS2 expression in prostate cancer. We found direct interaction between MTA1 and ETS2 in cells expressing ectopic MTA1 and ETS2. Interestingly, the prostate-specific Pten heterozygous mice, when fed with diet supplemented with pterostilbene, a natural pharmacological inhibitor of MTA1, showed a decrease in ETS2 mRNA and protein levels, perhaps due to decreased recruitment of MTA1 onto the ETS2 promoter. These results suggest that MTA1 functions as a coactivator for regulating ETS2 expression in prostate cancer at the transcriptional level and co-operates with ETS2 to promote prostate cancer progression. At the same time, pterostilbene may become a novel chemopreventive and therapeutic candidate for clinical development in prostate cancer due to its ability to target the MTA1-ETS2 axis. Citation Format: Avinash Kumar, Swati Dhar, Nasir Butt, Agnes Rimando, Luis Martinez, Anait Levenson. The role and regulation of MTA1-ETS2 axis in prostate 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 1861.
<i>In Vivo</i> FRET Imaging of Tumor Endothelial Cells Highlights a Role of Low PKA Activity in Vascular Hyperpermeability
Authors: Fumio Yamauchi, Yuji Kamioka, Tetsuya Yano, Michiyuki Matsuda
Journal: Cancer Research (2016)

Abstract Vascular hyperpermeability is a pathological hallmark of cancer. Previous in vitro studies have elucidated roles of various signaling molecules in vascular hyperpermeability; however, the activities of such signaling molecules have not been examined in live tumor tissues for technical reasons. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Förster resonance energy transfer, we examined the activity of protein kinase A (PKA), which maintains endothelial barrier function. The level of PKA activity was significantly lower in the intratumoral endothelial cells than the subcutaneous endothelial cells. PKA activation with a cAMP analogue alleviated the tumor vascular hyperpermeability, suggesting that the low PKA activity in the endothelial cells may be responsible for the tumor-tissue hyperpermeability. Because the vascular endothelial growth factor (VEGF) receptor is a canonical inducer of vascular hyperpermeability and a molecular target of anticancer drugs, we examined the causality between VEGF receptor activity and the PKA activity. Motesanib, a kinase inhibitor for VEGF receptor, activated tumor endothelial PKA and reduced the vascular permeability in the tumor. Conversely, subcutaneous injection of VEGF decreased endothelial PKA activity and induced hyperpermeability of subcutaneous blood vessels. Notably, in cultured human umbilical vascular endothelial cells, VEGF activated PKA rather than decreasing its activity, highlighting the remarkable difference between its actions in vitro and in vivo. These data suggested that the VEGF receptor signaling pathway increases vascular permeability, at least in part, by reducing endothelial PKA activity in the live tumor tissue. Cancer Res; 76(18); 5266–76. ©2016 AACR.
Abstract 536: Excessive HCK kinase activity in the tumor stroma promotes colorectal cancer progression
Authors: Matthias Ernst, Ashleigh Poh, Frederic Masson, Tracy Putoczki, Robert O’Donoghue
Journal: Cancer Research (2016)

Abstract Excessive activation of the myeloid-specific Src-family kinase Hematopoietic Cell Kinase (HCK) acts as a tumor intrinsic oncogene by promoting proliferation and survival of immune cells, and confers a poor prognosis for leukemia. However, the role of HCK in the tumor stroma of solid malignancies remains unexplored. We analyzed the expression level of HCK in matched biopsies from sporadic colorectal cancer patients and observed elevated HCK phosphorylation in tumors compared to unaffected colons. Analysis of corresponding RNAseq data revealed a striking correlation between tumors with high HCK gene expression and a gene signature indicative of a tumor-promoting alternatively-activated macrophage (AAM) endotype. To functionally assess this observation, we exploited HckCA mice [Ernst et al., J Exp Med 2002] that express a constitutively active form of Hck as a knockin mutation, and subjected these mice to a chemically-induced model of sporadic colorectal cancer. HckCA mice developed more and larger tumors compared to wild-type (WT) animals, and this was associated with a significant bias towards CD206+ AAMs in tumors of HckCA mice without affecting the total number of tumor-associated leukocyte and lymphocytes. Likewise, adoptive bone-marrow transfer experiments revealed enhanced tumor formation and AAM differentiation in WT mice reconstituted with HckCA bone marrow, with a reciprocal decrease of these parameters in HckCA mice reconstituted with WT marrow. Finally, pharmacologic targeting of the catalytic activity of Hck with a small molecule inhibitor significantly reduced tumor progression and impaired AAM polarisation. Collectively, our findings suggest that excessive Hck activity in the tumor stroma promotes the progression of solid cancers by modulating the endotype of tumor-associated myeloid cells. Therefore, Hck represents a rational therapeutic target for macrophage re-education in solid cancers by limiting polarization of tumor-promoting AAM. Citation Format: Matthias Ernst, Ashleigh Poh, Frederic Masson, Tracy Putoczki, Robert O’Donoghue. Excessive HCK kinase activity in the tumor stroma promotes colorectal cancer progression. [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 536.
The Pharmacogenomic Association of Fcγ Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Rodrigo Cartin‐Ceba, Divya Indrakanti, Ulrich Specks, John H. Stone, Gary S. Hoffman, Cees G. M. Kallenberg, Carol A. Langford, Peter A. Merkel, Robert F. Spiera, Paul A. Monach, E. William St.Clair, Philip Seo, Nadia K. Tchao, Steven R. Ytterberg, Paul G. Brunetta, Huijuan Song, Dan Birmingham, Brad H. Rovin
Journal: Arthritis & Rheumatology (2016)

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively.Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests.No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission (P = 0.01). The 519AA genotype predicted complete remission (P = 0.006) and a shorter time to complete remission (P < 0.001).The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy.
Abstract 1879: Structural and biochemical characterization of farnesylated and methylated KRAS-membrane interactions
Authors: Que Van, William K. Gillette, Dominic Esposito, Rodolfo Ghirlando, Frank Heinrich, Andrew G. Stephen
Journal: Cancer Research (2016)

Abstract KRAS4b, which is frequently mutated in pancreatic, colon and lung cancers, is processed in several enzymatic steps that results in the addition of a farnesyl and a methyl group to the terminal cysteine residue. Plasma membrane localization of KRAS4b requires this processing along with a polybasic stretch of lysines within the hypervariable region. KRAS4b can bind to RAF-RBD in solution but membrane bound KRAS4b is required for RAF-kinase activation. In order to determine why membrane interaction of KRAS4b is required for MAPK signal transduction we under took a structural and biochemical analysis of KRAS4b-membrane interactions. We have developed methods using an engineered baculovirus for the insect cell production of farnesylated and methylated KRAS4b (KRAS4b-FME) and this material was used in these studies. We have demonstrated that the stable interaction of KRAS4b-FME to lipid Nanodiscs and tethered lipid bilayers is dependent on the presence of anionic phospholipids. Using analytical ultracentrifugation we have evaluated the binding stoichiometry of KRAS4b-FME with Nanodiscs. In addition we have used neutron reflectivity to determine the orientation of KRAS4b-FME on tethered lipid bilayers. Citation Format: Que Van, William K. Gillette, Dominic Esposito, Rodolfo Ghirlando, Frank Heinrich, Andrew G. Stephen. Structural and biochemical characterization of farnesylated and methylated KRAS-membrane interactions. [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 1879.
Abstract 3625: Beyond SNPs: Utilizing NGS methods to detect copy number alterations at high sensitivity in clinical cancer samples
Authors: Sharanya Raghunath, Jackie Wayne, Aimee Shamo, Patrick Bradley, Moises Hernandez Abanto, David Loughmiller, Jason Gillman, Derrick S. Haslem, Gary Stone, Pravin Mishra, Lincoln D. Nadauld
Journal: Cancer Research (2016)

Abstract The emergence of novel technologies, including Next-Generation Sequencing, has enabled the identification of actionable variants in clinical specimens, which can then be targeted with molecular therapeutics in a precision medicine approach. In human cancers, Single Nucleotide Polymorphisms (SNPs) have become powerful predictors of response to certain targeted therapies. However, Copy Number Alterations (CNAs) also represent a major class of clinically actionable variants that are frequently identified in clinical cancer samples. CNAs account for more than one third of all actionable mutations. A major question in the clinical application of technologies such as NGS is whether CNAs are faithfully detected; a particularly important question given the prevalence of actionable CNAs in cancer samples. To address this question we prepared tumor samples from eleven distinct patients and compared CNA detection on two different NGS platforms. As an orthogonal method for validation, we compared the CNA detection results to Fluorescent In Situ Hybridization (FISH) performed on the same samples. We observed 20 copy number amplification events across the eleven patient samples according to FISH analysis. By comparison, our internal NGS assay, termed ICG100, detected 19/20 (94%) amplification events, whereas an external, commercially available NGS-based test detected only 12/20 (59%) amplification events. Of the seven amplification events that were not identified by the external NGS test, six were considered clinically actionable variants. These findings highlight the discrepancies that exist amongst NGS library preparation chemistries and their abilities to accurately detect CNAs. The relevance of these findings is particularly underscored by the clinically actionable nature of the variants that were discordantly detected, including a high-level ERBB2 amplification. Citation Format: Sharanya Raghunath, Jackie Wayne, Aimee Shamo, Patrick Bradley, Moises Hernandez Abanto, David Loughmiller, Jason Gillman, Derrick S. Haslem, Gary Stone, Pravin Mishra, Lincoln D. Nadauld. Beyond SNPs: Utilizing NGS methods to detect copy number alterations at high sensitivity in clinical cancer samples. [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 3625.