tbuckley/cabot-search huggingface dataset:
Abstract 7: Discovery of OICR-10268: A potent and selective BCL6 inhibitor
Authors: Iain D. Watson, Methvin Isaac, Brian Wilson, Anh Chau, Justin Morin, Pandiaraju Subramanian, Ahmed Mamai, Babu Joseph, Michael Prakesch, David Uehling, Ayome Abibi, Richard Marcellus, Craig Strathdee, Ratheesh Subramaniam, Brigitte Theriault, Jeffrey Winston, Manuel Chan, Carly Griffin, Herman Cheung, Taira Kiyota, Elijus Undzys, Ahmed Aman, Gennady Poda, Doug Kuntz, Neil C. Pomroy, Gil G. Privé, Rima Al-awar
Journal: Cancer Research (2019)

Abstract The transcription factor B cell lymphoma 6 (BCL6) is required for the generation of an effective humoral immune response through the development and maintenance of germinal centers (GCs). The inhibition of the protein−protein interaction between BCL6 and its corepressors has been implicated as a therapeutic target for diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin’s lymphoma (NHL). Using structure-based drug design, we initiated a program to identify novel BCL6 inhibitors. We identified a high micromolar virtual screening hit which was then optimized for potent biophysical binding and anti-proliferative cellular activity resulting in the identification of OICR-10268, a potent and selective Bcl6 inhibitor. Citation Format: Iain D. Watson, Methvin Isaac, Brian Wilson, Anh Chau, Justin Morin, Pandiaraju Subramanian, Ahmed Mamai, Babu Joseph, Michael Prakesch, David Uehling, Ayome Abibi, Richard Marcellus, Craig Strathdee, Ratheesh Subramaniam, Brigitte Theriault, Jeffrey Winston, Manuel Chan, Carly Griffin, Herman Cheung, Taira Kiyota, Elijus Undzys, Ahmed Aman, Gennady Poda, Doug Kuntz, Neil C. Pomroy, Gil G. Privé, Rima Al-awar. Discovery of OICR-10268: A potent and selective BCL6 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 7.
SAT0618 BASELINE CHARACTERISTICS AND TREATMENTS AMONG PATIENTS WITH RHEUMATOID ARTHRITIS: THE CREDIT STUDY IN CHINA, 2016-2018
Authors: Nan Jiang, Mengtao Li, Yanhong Wang, Jiuliang Zhao, Qian Wang, Xinping Tian, Hanjun Wu, MA Xiao, Lujing Zhan, Xiaofeng Zeng
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Rheumatoid Arthritis (RA) has been a huge public health issue among the Chinese population, but little is known about the current treatments among RA patients, especially with different disease activity levels. <h3>Objectives:</h3> To describe the baseline characteristics among all RA patients registered in the Chinese Registry of rhEumatoiD arthrITis (CREDIT) and the treatment patterns by patients' disease status. <h3>Methods:</h3> A total of 25,191 RA patients registered in CREDIT from Nov, 2016 to Apr, 2018 were enrolled. Patients' baseline characteristics of demographics, disease characteristics, comorbidities, as well as treatment agents for RA were abstracted for analysis. <h3>Results:</h3> The mean age of patients was 53.0 years and 79.9% of them were female. The median disease duration from diagnosis was 2.0 years. The proportions of moderate/high disease activity according to the Disease Activity Score-28 joint count using C-reactive protein (DAS28-CRP&gt;3.2) and Clinical Disease Activity Index (CDAI&gt;10) were 76.1% and 81.7%, respectively. Among those patients with treatment records, a similar conventional systematic disease-modifying antirheumatic drugs (cDMARDs) usage was observed in remission/low activity patients and moderate/high activity patients categorized by DAS28-CRP. The results showed that 1639 (29.9%) remission/low activity patients and 4948 (28.3%) moderate/high activity patients received csDMARD monotherapy, while more combination therapies were prescribed in both groups (57.2% vs 55.1%, respectively). Furthermore, 337 (6.2%) patients received biologic disease-modifying antirheumatic drugs (bDMARDs) in remission/low activity group, while 1021 (5.9%) patients received bDMARDs in moderate/high activity group. In terms of tsDMARDs (only tofacitinib was approved in China), the proportions of usage were lower for remission/low activity patients (0.2%) than for the moderate/high activity patients (0.3%). On the other hand, the proportion of glucocorticoids usage in remission/low activity patients (15.5%) was lower than in moderate/ high activity patients (21.3%). <h3>Conclusion:</h3> Over three-quarters of RA patients registered in CREDIT were in moderate/high disease activity. csDMARDs are the most frequently used medications for RA in China. <h3>Disclosure of Interests:</h3> Nan Jiang: None declared, Mengtao Li: None declared, Yanhong Wang: None declared, Jiuliang Zhao: None declared, Qian Wang: None declared, Xinping Tian: None declared, Hanjun Wu Employee of: Employee of Eli Lilly &amp; Co., Xiao Ma Employee of: Eli lilly Employee, Lujing Zhan Employee of: Employee of Eli Lilly &amp; Co., Xiaofeng Zeng: None declared
Abstract 1643: Discovery pipeline of cancer transcriptomic biomarkers using machine learning
Authors: Eileen Kim
Journal: Cancer Research (2019)

Abstract Introduction: Cancer affects millions of people and causes nearly 1 in 6 deaths worldwide. Precision oncology holds potential in guiding cancer treatment on a molecular basis and elucidating targetable cancer pathways. This study aims to create a discovery pipeline that uses cancer patients’ transcriptomes and machine learning algorithms to predict cancer patient survival. Methods: Transcriptomic and phenotypic data from cancer patients were downloaded from The Cancer Genome Atlas (TCGA). Initial genes were selected using univariate cox proportional hazard models to predict overall survival across all cancer types. Co-expressed selected genes were clustered, creating gene sets per cancer subtype. Then, an amalgam of LASSO and elastic-net regularized generalized linear models (GLMNET), gene bootstrapping, random forest without/with shadow features (Boruta), and recursive feature elimination were used. Monte Carlo iterations were performed for GLMNET to assess model stability and over-/underfitting. Results: The highest hazard ratios (HRs) and lowest p-values resulted from the univariate cox proportional hazards model (e.g. for the RASGEF1A gene in a uterine serous carcinoma model, HR=2.8e8, p=0.005) and subsequent GLMNET models (e.g. 392 genes for uterine endometrioid carcinoma, HR=2.89e8, p=0.00873). Boruta before GLMNET yielded lower HRs and higher p-values (e.g. 11 genes for uterine serous carcinoma, HR=2, p=0.0517). Bootstrapping genes before GLMNET generally yielded much lower HRs and higher p-values. Conclusions: We were able to model survival risk in cancer patients with a variety of methods. The best method so far is univariate gene selection and GLMNET, although random forest is promising. Next steps include exploring random forest models further, investigating the biology of prognostic models, using disease-specific survival, analyzing possible confounders, using Breslow-Wilcoxon or accelerated failure time models, replacing histological with molecular-signature-based cancer subtypes, and exploring alternative methods for prognosis prediction. Supported by the Medical Scholars Program, Medical College of Georgia, Augusta, GA. Citation Format: Eileen Kim. Discovery pipeline of cancer transcriptomic biomarkers using machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1643.
Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies
Authors: Emanuela Dylgjeri, Christopher McNair, Jonathan F. Goodwin, Heather K. Raymon, Peter A. McCue, Ayesha A. Shafi, Benjamin E. Leiby, Renée de Leeuw, Vishal Kothari, Jennifer J. McCann, Amy C. Mandigo, Saswati N. Chand, Matthew J. Schiewer, Lucas J. Brand, Irina Vasilevskaya, Nicolas Gordon, Talya S. Laufer, Leonard G. Gomella, Costas D. Lallas, Edouard J. Trabulsi, Felix Y. Feng, Ellen H. Filvaroff, Kristin Hege, Dana Rathkopf, Karen E. Knudsen
Journal: Clinical Cancer Research (2019)

DNA-dependent protein kinase catalytic subunit (DNA-PK) is a pleiotropic kinase involved in DNA repair and transcriptional regulation. DNA-PK is deregulated in selected cancer types and is strongly associated with poor outcome. The underlying mechanisms by which DNA-PK promotes aggressive tumor phenotypes are not well understood. Here, unbiased molecular investigation in clinically relevant tumor models reveals novel functions of DNA-PK in cancer.Experimental Design: DNA-PK function was modulated using both genetic and pharmacologic methods in a series of in vitro models, in vivo xenografts, and patient-derived explants (PDE), and the impact on the downstream signaling and cellular cancer phenotypes was discerned. Data obtained were used to develop novel strategies for combinatorial targeting of DNA-PK and hormone signaling pathways.Key findings reveal that (i) DNA-PK regulates tumor cell proliferation; (ii) pharmacologic targeting of DNA-PK suppresses tumor growth both in vitro, in vivo, and ex vivo; (iii) DNA-PK transcriptionally regulates the known DNA-PK-mediated functions as well as novel cancer-related pathways that promote tumor growth; (iv) dual targeting of DNA-PK/TOR kinase (TORK) transcriptionally upregulates androgen signaling, which can be mitigated using the androgen receptor (AR) antagonist enzalutamide; (v) cotargeting AR and DNA-PK/TORK leads to the expansion of antitumor effects, uncovering the modulation of novel, highly relevant protumorigenic cancer pathways; and (viii) cotargeting DNA-PK/TORK and AR has cooperative growth inhibitory effects in vitro and in vivo.These findings uncovered novel DNA-PK transcriptional regulatory functions and led to the development of a combinatorial therapeutic strategy for patients with advanced prostate cancer, currently being tested in the clinical setting.
Caution About Displaying State-Level Differences in the Prevalence of Autism Spectrum Disorder
Authors: Michael D. Kogan, Catherine J. Vladutiu, James M. Perrin
Journal: JAMA Pediatrics (2019)

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USA aid policy and induced abortion in sub-Saharan Africa: an analysis of the Mexico City Policy
Authors: Nina Brooks, Eran Bendavid, Grant Miller
Journal: The Lancet Global Health (2019)

The Mexico City Policy, first announced by US President Ronald Reagan and since lifted and reinstated by presidents along partisan lines, prohibits US foreign assistance to any organisation that performs or provides counselling on abortion. Many organisations affected by this policy are also providers of modern contraception. If the policy reduces these organisations' ability to supply modern contraceptives, it could have the unintended consequence of increasing abortion rates.We empirically examined patterns of modern contraception use, pregnancies, and abortion among women in 26 countries in sub-Saharan Africa in response to the reinstatement and subsequent repeal of the Mexico City Policy across three presidential administrations (William Clinton, George W Bush, and Barack Obama). We combine individual-level data on pregnancies and abortions from 743 691 women, country-year data on modern contraception use, and annual data on development assistance for family planning and reproductive health in a difference-in-difference framework to examine relative changes in use of modern contraception, pregnancy, and abortion in response to the policy.We found that when the Mexico City Policy was in effect (2001-08), abortion rates rose among women in countries highly exposed to the policy by 4·8 abortions per 10 000 woman-years (95% CI 1·5 to 8·1, p=0·0041) relative to women in low-exposure countries and relative to periods when the policy was rescinded in 1995-2000 and 2009-14, a rise of approximately 40%. We found a symmetric reduction in use of modern contraception by 3·15 percentage points (relative decrease of 13·5%; 95% CI -4·9 to -1·4; p=0·0006) and increase in pregnancies by 3·2 percentage points (relative increase of 12%; 95% CI 1·6 to 4·8; p<0·0001) while the policy was enacted.Our findings suggest that curbing US assistance to family planning organisations, especially those that consider abortion as a method of family planning, increases abortion prevalence in sub-Saharan African countries most affected by the policy.The William and Flora Hewlett Foundation, the Doris Duke Charitable Foundation, the David and Lucile Packard Foundation, and the Stanford Earth Dean's Fellowship.
Abstract 3576: MALAT1 is essential for A-NHEJ pathway choice during B cell immunoglobulin class switch recombination
Authors: Jianjun Zhao, Yi Hu, Jianhong Lin, Hua Fang
Journal: Cancer Research (2019)

Abstract Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) has been found high expressed in multiple cancer type including B cell lymphoma and multiple myeloma. In human cancer murine models, deficiency of MALAT1 reduce the tumor burden and malignancy phynotype. We have identified MALAT1 in alternative-non-homozygous end joining(A-NHEJ) pathway by binding to PARP1 and LIG3 in multiple myeloma cells, two key components of the A-NHEJ protein complex. To investigate requirments for MALAT1 in A-NHEJ pathway, by using MALAT1 deficient mice, we found that the contribution of MALAT1 in the context of AID induced DNA breaks in CSR of B cells in mice. MALAT1 is required for A-NHEJ DNA repair pathway, but not the NHEJ pathway, which is the major DNA repair pathway for CSR. To further prove the hypothesis that MALAT1 promote A-NHEJ pathway in B cells, we have engineered mice that conditionally overexpress MALAT1 in B lymphocytes confers a strong A-NHEJ activity in CSR. More importantly, we also found IgH/c-myc translocations are promoted in MALAT1 B cell specific transgenic mice. Thus, we identified MALAT1 as a critical noncoding RNA in regulating A-NHEJ pathway during CSR. Citation Format: Jianjun Zhao, Yi Hu, Jianhong Lin, Hua Fang. MALAT1 is essential for A-NHEJ pathway choice during B cell immunoglobulin class switch recombination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3576.
Abstract 1227: Immune modulatory effect of pramlintide for cutaneous squamous cell carcinoma treatment
Authors: Leticia Tordesillas, Rebecca Hesterberg, Ivannie Ortiz-Rivera, Brittney R. Sell, Omar Chavez Chiang, Kimberly T. Nguyen, Brian L. Murphy, Pearlie K. Burnette, Elsa R. Flores, Kenneth Y. Tsai
Journal: Cancer Research (2019)

Abstract Cutaneous squamous cell carcinoma (cuSCC) accounts for 15-20% of skin cancers. Treatment of cuSCC with pramlintide, a synthetic analog of the hormone amylin, is currently under investigation in mouse models and human clinical trials. In cancer cells, pramlintide inhibits glycolysis, resulting in cell death and tumor regression. In order to investigate the potential use of pramlintide in combinatory therapies with checkpoint inhibitors, we aimed to study the immune modulatory effect of pramlintide in an immune competent mouse model of spontaneous ultraviolet radiation-induced cuSCC, as well as its effect on human T cells in vitro. To induce cuSCC, SKH-1 hairless mice were subjected to ultraviolet radiation until at least one tumor reached &amp;gt;4mm of diameter. Mice were then treated with 45 µg/kg of pramlintide or vehicle control for 10 days, every other day. Skin-draining lymph nodes, spleen and tumors were harvested for immunophenotyping of the T cell and myeloid compartment by flow cytometry. While the proportion of CD103+ dendritic cells (DCs) and CD3+ T cells remained constant after pramlintide treatment, a significant decrease in the proportion of both monocytic and granulocytic myeloid-derived suppressor cells (m-MDSCs and g-MDSCs) was observed relative to vehicle-control treated mice. Interestingly, pramlintide abolished m-MDSC differentiation from bone marrow progenitors in vitro suggesting that pramlintide may regulate a pathway necessary for m-MDSC development. Purified human CD3+ T cells activated in the presence of pramlintide exhibited a time-dependent increase in intracellular and secreted IFN-γ. Therefore, pramlintide may have immune modulatory effects based on both a reduction in myeloid-dependent suppression and a direct stimulatory effect on T cells that would culminate in superior anti-tumor T cell responses that augment immunotherapeutic approaches for the treatment of cuSCC. Citation Format: Leticia Tordesillas, Rebecca Hesterberg, Ivannie Ortiz-Rivera, Brittney R. Sell, Omar Chavez Chiang, Kimberly T. Nguyen, Brian L. Murphy, Pearlie K. Burnette, Elsa R. Flores, Kenneth Y. Tsai. Immune modulatory effect of pramlintide for cutaneous squamous cell carcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1227.
An objective based model of published treatment options for relapsed or refractory (R/R) peripheral t-cell lymphoma (PTCL): An evidence-based decision-making approach.
Authors: Enrica Marchi, Kensei Tobinai, Dai Maruyama, Hirokazu Nagai, Owen A. O'Connor
Journal: Journal of Clinical Oncology (2019)

e19048 Background: PTCL are rare diseases with a poor prognosis. Front line therapy achieves CR in 30% to 60% and OS of 25%. Patients with R/R disease have an even worse prognosis. There is no consensus on the management of R/R disease because evidence supporting most treatment approaches is modest. Many approaches are often not supported by literature, and categorizations regarding efficacy and toxicity without attention to details are ignored. Treatments that have achieved regulatory approval with stringent independent assessment of pathology and response are viewed as less established, or equivalent to smaller published experiences. In the effort to take a critical and comprehensive evidence-based approach to available standards in R/R PTCL we developed an objective scoring system for all types of studies published in the literature (eg randomized phase 3, case match control, phase 2, phase 1, case reports and small series) to aid decision-making based on an assessment of all the available data. Methods: An extensive review on PubMed of clinical trials published in literature for R/R PTCL was performed. A rigorous scoring system based on a survey from 100 authorities in the field to quantitate scientific impact of each study based was developed. These include: type of study (randomized phase 3, case match control analysis, phase 2 weighted based on number of PTCL patients [ &gt; 100 vs &lt; 100 patients], phase 1 with &gt; 5 or &lt; 5 PTCL patients enrolled, and retrospective); weighting for use of central pathology or response review; weighting for detailed study metrics (ORR, CR, DoR, PFS). The scoring system included a penalty for omission detail. The proposed scoring system was evaluated by a panel of experts. The scoring system was modified based on recommendations made by 2 or more panel members. Results: We identified 58 publications between 2004 and 2018. The scoring system spanned from 0 to 9. Only 12 of the 58 studies had a score above 5; 15 of 58 had a score between 1 - 5; remaining publications scored 0 - 1. Conclusions: Our analysis suggests practice patterns are based on studies with low priority scores, and underweight robust clinical experiences. This analysis aims to produce an evidenced based approach for R/R PTCL.
Abstract 146: Multiple modalities of NanoString GeoMx™ Digital Spatial Profiler allow for spatially-resolved, multiplexed quantification of protein and mRNA distribution and abundance
Authors: Gokhan Demirkan, Elena Viboch, Chris Merritt, Giang Ong, Kristi Zevin, Kristina Sorg, Lindy Irving, Dwayne Dunaway, Gary K. Geiss, Joseph Beechem
Journal: Cancer Research (2019)

Abstract Characterization of the spatial distribution and abundance of proteins and mRNAs with morphological context within tissues enables a better understanding of biological systems in many research areas, including immunology and oncology. However, it has proven difficult to perform such studies in a highly multiplexed manner. To address this unmet need, we have developed a novel optical-barcode based microscope and tissue-sampling platform designed to simultaneously analyze hundreds of proteins or mRNAs on a single FFPE section from distinct tissue spatial regions (GeoMxTM Digital Spatial Profiler, DSP). Here, we present a series of modalities and associated applications for the GeoMxTM DSP platform and its integrated software. First, geometric profiling can be utilized by drawing automated circles, squares or even manual hand-drawn polygons as regions of interest (ROI) to characterize tissue heterogeneity. Second, gridded profiling offers high resolution unbiased tumor profiling by placing a grid on tissues and separately analyzing each segment in the grid. Third, contour profiling employs concentric rings, or any custom shape at a growing distance from a site of interest. Finally, segment and rare cell profiling exploits fluorophore-conjugated antibodies to profile specific cell types. These techniques can be used to discover drug mechanism of action or immune activation status, as well as to facilitate prediction of treatment response and disease progression or investigation of specific rare cell populations’ molecular profiles. Using these multiple modalities, we spatially resolve protein and mRNA expression over 30 immune targets on FFPE tissue sections from various organs, including colon and tonsil. We demonstrate multiplexed detection from discrete regions within a tumor (tumor center and immune invasive margin), enabling systematic interrogation of immune activity in FFPE samples. Finally, we present the utility of each modality under different scenarios. Citation Format: Gokhan Demirkan, Elena Viboch, Chris Merritt, Giang Ong, Kristi Zevin, Kristina Sorg, Lindy Irving, Dwayne Dunaway, Gary K. Geiss, Joseph Beechem. Multiple modalities of NanoString GeoMx™ Digital Spatial Profiler allow for spatially-resolved, multiplexed quantification of protein and mRNA distribution and abundance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 146.