tbuckley/cabot-search huggingface dataset:
Practice patterns in the use of adjuvant therapy for post-menopausal early-stage breast cancer in the pre- and post-Onco<i>type</i> DX era.
Authors: Asma Latif, Alexander C. Small, Erin L. Moshier, Kerin B. Adelson, George Raptis, James H. Godbold, William K. Oh, Matt D. Galsky
Journal: Journal of Clinical Oncology (2012)

e21032 Background: Personalized oncology offers the promise of selectively applying therapeutics to patients most likely to benefit, while sparing those unlikely to benefit from potentially toxic therapies. Oncotype DX is a 21-gene assay utilized to identify hormone-receptor positive (HR+), node negative, breast cancer (Br CA) patients who may be successfully treated with adjuvant hormonal therapy alone. We hypothesized that practice patterns with adjuvant therapy have changed since the commercial availability of Oncotype DX in 2004. Methods: The Public National Cancer Database was queried to identify patients age ≥ 50 with stage I or II Br CA diagnosed from 2000 to 2008. Patients were classified by adjuvant therapy including hormone, chemotherapy, hormone and chemotherapy, and no hormone or chemotherapy. Log-binomial regression was used to estimate prevalence ratios for the proportion of patients receiving adjuvant therapies from 2000-2003 compared to 2004-2008. Results: 833,018 patients age ≥ 50 with stage I or II Br CA were identified. The application of adjuvant therapies for the periods pre- and post-availability of Oncotype DX are detailed in the Table. Conclusions: There has been significant increase (13%) in the use of hormonal therapy alone as adjuvant therapy for patients age ≥ 50 with HR+ stage I-II Br CA since commercial availability of Oncotype DX. While this has been slightly offset by a decrease in the use of chemotherapy plus hormonal therapy, there has been a larger decrease in the use of “no adjuvant therapy”. Data regarding predictive biomarkers should be captured by registries in an effort to determine the true impact of these tests on treatment utilization. [Table: see text]
Abstract 3944: MKI-1 is a small molecule inhibitor of MASTL with antitumor and radiosensitizer activity in breast cancer cells
Authors: Ah-Young Kim, Jae-Sung Kim
Journal: Cancer Research (2019)

Abstract Although microtubule-associated serine threonine kinase like (MASTL) is an emerging target for selective anticancer treatment, a small-molecule inhibitor of MASTL with antitumor activity had not been reported yet. This study showed the new MASTL inhibitor, MKI 1 (MASTL Kinase Inhibitor 1), with antitumor activity and radiosensitizing effect in breast cancer in vitro and in vivo. MKI 1 was identified and validated its inhibitory activity to MASTL by in silico and in vitro analysis, respectively. MKI 1 inhibited phosphorylated ENSA, a direct substrate of MASTL, but not the other AGC kinases such as Akt signaling in breast cancer cells. In addition, MKI 1 reduced various oncogenic properties of breast cancer cells rather than normal breast cells. Furthermore, MKI 1 increased the radiosensitivity of breast cancer cells and breast cancer stem cells in response to irradiation. We also confirm the in vivo antitumor activity and radiosensitizing effects of MKI 1 in breast tumor xenograft model. Therefore, our results provide the new line of a small-molecule inhibitor of MASTL, MKI 1, with the antitumor and radiosensitizer activity in breast cancer in vitro and in vivo. Citation Format: Ah-Young Kim, Jae-Sung Kim. MKI-1 is a small molecule inhibitor of MASTL with antitumor and radiosensitizer activity in breast cancer cells [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 3944.
Abstract 1640: Deep learning classification of neuro-oncology medical documents
Authors: Michael Wells, Thais Sabedot, Tathiane Malta, James Snyder, Laila Poisson, Houtan Noushmehr
Journal: Cancer Research (2019)

Abstract Introduction Precision medicine and big data for cancer discovery requires well curated indexed critical health care data, however to date limited resources exist that successfully parse out unstructured clinical data in neuro-oncology. Current practice relies on time consuming manual extraction by researchers or clinicians resulting in data inconsistency and limitation in data set volume. Rule-based natural language processing algorithms could be used for simple consistent text, but medical documents are created longitudinally by multiple people across long periods of time resulting in inconsistencies and semantic heterogeneity that render rule-based techniques insufficient. Methods We applied a deep learning text classification method to multiple clinical document categories including clinical pathology reports and a text based clinical database spanning 17 years of clinical narratives with approximately 4000 unique cases. For this study we identified clinically relevant molecular criteria for glioma outlined in the WHO 2016 CNS classification of tumors including IDH mutation, MGMT methylation, and 1p19q co-deletion status. Using a convolutional neural network with two densely connected layers of 30 rectified linear nodes we were able to classify patients into their respected molecular cohort with an accuracy of 98%. Conclusion Parsing of unstructured text based clinical narratives and pathology reports using convolutional neural networks is a promising method to extract heterogeneous molecular data in neuro-oncology for large scale data analysis. Citation Format: Michael Wells, Thais Sabedot, Tathiane Malta, James Snyder, Laila Poisson, Houtan Noushmehr. Deep learning classification of neuro-oncology medical documents [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 1640.
Abstract 4000: Development of a patient navigation training program for the Caribbean context
Authors: Kimlin T. Ashing, KImberly Badal
Journal: Cancer Research (2019)

Abstract Introduction For the Caribbean context, a patient navigator (PN) is one who is responsible for coordinating and streamlining care in a complex cancer care continuum by providing support in physical, mental and emotional challenges; educating and empowering patients in their journey; tracking patient medical records electronically and addressing barriers to care. As a first step to introducing this role to the Caribbean, a comprehensive training program for new navigators was developed and conducted. Methods A multi-disciplinary steering committee consisting of a behavioral scientist, two oncology registered nurses and educators, a clinical psychologist, two cancer survivors, a cancer researcher, a physician and an experienced oncology nurse navigator was formed in Trinidad and Tobago. The steering committee had these objectives: (i) develop a comprehensive list of PN core competencies; (ii) determine PN skill requirements; (iii) develop and execute a training curriculum that met the PN core competencies. Results Two categories of navigators and requisite skill requirements were developed for each (Table 1). Three skill domains were defined as patient navigator skills, research skills and professional skills. Each domain was then divided into specific competencies which translated into 11 curriculum topics. Candidates who met the skill requirements filled a form-based application, provide a curriculum vitae and completed 0.5hr scenario-based interview. A 5-day, 30 contact hour patient navigation training program was successfully conducted with candidates from 4 Caribbean territories. Results of the pre- and post- test assessment as well as the training evaluation will be reported in the presentation. Conclusion A productive international collaboration between City of Hope an NCI designated Comprehensive Cancer Center and CCRI a civil society cancer organization successfully developed and conducted a comprehensive program to train patient navigators for the Caribbean context. Table 1:Skill requirements for oncology nurse navigators and lay navigatorsOncology Nurse NavigatorLay NavigatorPrimary Skill RequirementsOncology-trained Registered Nurse. Registered Nurse with 2 years clinical experience in OncologyCancer survivor. Care giverAlternative Skill Requirements SkillsRetired medical personnel. Any Registered NurseAny person with interest, holding a minimum Bachelor degree in a related area of expertise such as counselling pharmacy, psychology, social work etc. Citation Format: Kimlin T. Ashing, KImberly Badal. Development of a patient navigation training program for the Caribbean context [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 4000.
Abstract 300: A new combination therapy to treat metastatic breast cancer
Authors: Bahram Sharif-Askari, Raquel Aloyz, Lawrence Panasci
Journal: Cancer Research (2019)

Abstract Poly (ADP-ribose) polymerase (PARP) resulting poly (ADP-ribosyl)ation is an early player in modification of proteins detected at single strand breaks and double strand breaks contributing to DNA repair. PARP1, 2 and 3 are involved in this process. However, PARP3 is unique in that, it is also required for efficient mitotic progression, specifically in stabilization of the mitotic spindle. The vinca alkaloids such as vinorelbine, arrest cells in metaphase due to inhibition of the assembly and dynamics of microtubules. Nontoxic concentrations of 2 PARP3 inhibitors, ME-0328 and olaparib, sensitized various her-2 negative and triple negative breast cancer cell lines greater than or equal to 10 fold to vinorelbine associated with potentiation of vinorelbine’s interaction with tubulin and also vinorelbine-induced PARP3 inhibition, mitotic arrest, and apoptosis without evidence of a DNA repair mechanism involved in this sensitization (Sharif-Askari B et al. Breast Cancer Res Treat. 2018 Nov;172(1):23-32). Eribulin is a Halichondrin B analogue, an antitubulin drug, with a unique mechanism of action; it inhibits microtubule dynamics via a novel mechanism of action which seems to involve binding to a unique site on tubulin resulting in the suppression of microtubule polymerization without affecting depolymerization along with sequestration of tubulin into nonfunctional aggregate. After impressive results in phase III trials (including one of the rare trials to show prolongation of survival in comparison to standard of care in heavily pretreated metastatic breast cancer patients) the U.S. Food and Drug Administration approved eribulin for treatment of patients with metastatic breast cancer. PARP3 inhibitors again sensitized at least 5 fold her-2 negative and triple negative breast cancer cell lines to eribulin. We will do similar studies with eribulin as we have done with vinorelbine including in-vivo studies. These studies could define a new therapy in the treatment of metastatic triple negative and ER+/her-2 negative breast cancer. The inhibition of PARP3 may increase the sensitivity of tumor cells to mitotic spindle poison chemotherapies. Our results should stimulate development of specific PARP3 inhibitors for clinical use. Citation Format: Bahram Sharif-Askari, Raquel Aloyz, Lawrence Panasci. A new combination therapy to treat metastatic breast cancer [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 300.
Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates and humans
Authors: Josephine Jüttner, Arnold Szabo, Brigitte Gross-Scherf, Rei K. Morikawa, Santiago B. Rompani, Peter Hantz, Tamas Szikra, Federico Esposti, Cameron S. Cowan, Arjun Bharioke, Claudia P. Patino-Alvarez, Özkan Keles, Akos Kusnyerik, Thierry Azoulay, Dominik Hartl, Arnaud R. Krebs, Dirk Schübeler, Rozina I. Hajdu, Akos Lukats, Janos Nemeth, Zoltan Z. Nagy, Kun-Chao Wu, Rong-Han Wu, Lue Xiang, Xiao-Long Fang, Zi-Bing Jin, David Goldblum, Pascal W. Hasler, Hendrik P. N. Scholl, Jacek Krol, Botond Roska
Journal: Nature Neuroscience (2019)
Abstract 2744: Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer
Authors: Ivy X. Chen, Vikash P. Chauhan, Jessica Posada, Mei R. Ng, Michelle Wu, Pichet Adstamongkonkul, Peigen Huang, Neal Lindeman, Robert Langer, Rakesh K. Jain
Journal: Cancer Research (2019)

Abstract Metastatic breast cancers (mBCs) are largely resistant to immune checkpoint blockade, but the mechanisms remain unclear. Primary breast cancers are characterized by a dense fibrotic stroma, which is considered immunosuppressive in multiple malignancies, but the stromal composition of breast cancer metastases and its role in immunosuppression are largely unknown. Here we show that liver and lung metastases of human breast cancers tend to be highly fibrotic, and unlike primary breast tumors, they exclude cytotoxic T-lymphocytes (CTLs). Unbiased analysis of the TCGA database of human breast tumors revealed a set of genes that are associated with stromal T-lymphocyte exclusion. Among these we focused on CXCL12 as a relevant target based on its known roles in immunosuppression in other cancer types. We found that the CXCL12 receptor CXCR4 is highly expressed in both human primary tumors and metastases. To gain insight into the role of CXCL12/CXCR4 axis, we inhibited CXCR4 and found that CXCR4 blockade decreases fibrosis, alleviates solid stress, decompresses blood vessels, increases CTL infiltration, and decreases immunosuppression in murine mBC models. We confirmed that these immunosuppressive effects are dependent on cancer-associated fibroblast (CAF) signaling through genetic deletion of Cxcr4 in aSMA+ cells. Accordingly, CXCR4 inhibition more than doubles the response to immune checkpoint blockers in mice bearing mBCs. These findings demonstrate that CXCL12/CXCR4-mediated desmoplasia in mBC promotes immunosuppression and is a potential target for overcoming therapeutic resistance to immune checkpoint blockade in mBC patients. Citation Format: Ivy X. Chen, Vikash P. Chauhan, Jessica Posada, Mei R. Ng, Michelle Wu, Pichet Adstamongkonkul, Peigen Huang, Neal Lindeman, Robert Langer, Rakesh K. Jain. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer [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 2744.
Abstract 2783: <i>OMICS</i> analysis of breast cancer PDX tumors to determine CTC-cluster-specific signature in predicting breast cancer metastasis
Authors: Hariprasad Thangavel, Carmine De Angelis, Suhas Vasaikar, Raksha Bhat, Mohit Kumar Jolly, Lacey Elizabeth Dobrolecki, Jason T. George, Mario Giuliano, Michael Lewis, Herbert Levine, Bing Zhang, Rachel Schiff, Meghana V. Trivedi
Journal: Cancer Research (2019)

Abstract Circulating tumor cell clusters (CTCcl) have been shown to have a significantly higher metastatic potential compared to single CTCs and to predict long-term outcomes in breast cancer patients. A characterization of primary tumors that give rise to CTCcl hold significant promises for better diagnosis and may uncover targets for prevention and treatment of metastatic breast cancer. In our study, we utilized the available transcriptomic and proteomic data (RNA-Seq and RPPA) of 10 triple-negative breast cancer patient-derived xenograft (TNBC-PDX) transplantable models. The sample set consisted of 6 CTCcl-negative (-) and 4 CTCcl-positive (+) models. Genome-wide transcriptomic analysis revealed 549 differentially expressed genes in CTCcl+ TNBC-PDX models vs. CTCcl- models (316 up-regulated and 233 down-regulated, p&amp;lt;0.05). Gene set enrichment analysis (GSEA) terms significantly enriched (FDR&amp;lt;0.05) in CTCcl+ TNBC-PDXs included Cytoplasmic Ribosomal Proteins (NES=2.53), Angiogenesis (NES=1.95), Type II Interferon signaling (NES=-2.52), Antigen processing and presentation (NES=-2.38), TNF signaling pathway (NES=-2.04), Jak-STAT signaling pathway (NES=-1.91), and apoptosis (NES=-1.69). The proteomic analysis revealed elevated levels of Bcl2 expression in PDX tumors associated with CTCcl positivity, which substantiated the inhibited apoptosis pathway as seen in GSEA analysis. The increase in Bcl2 was also validated independently by IHC staining in primary PDX tumors that were CTCcl+. The distribution of EMT score based on the inferential EMT metric using canonical epithelial and mesenchymal markers was not significantly different between CTCcl+ and CTCcl- TNBC-PDX tumors suggesting no differential regulation of EMT in tumors that give rise to clusters versus only single cells. In summary, our results suggest that primary tumors with active anti-apoptotic and/or survival pathways may promote CTC clusters formation and increase the risk of distant metastasis. Citation Format: Hariprasad Thangavel, Carmine De Angelis, Suhas Vasaikar, Raksha Bhat, Mohit Kumar Jolly, Lacey Elizabeth Dobrolecki, Jason T. George, Mario Giuliano, Michael Lewis, Herbert Levine, Bing Zhang, Rachel Schiff, Meghana V. Trivedi. OMICS analysis of breast cancer PDX tumors to determine CTC-cluster-specific signature in predicting breast cancer metastasis [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 2783.
Abstract 2050: Cell penetrating peptide, ST101, disrupts ATF5 regulation of anti-apoptotic Bcl-2 family proteins, resulting in induction of cancer cell death in vitro and tumor growth inhibition/regression in vivo
Authors: Jim A. Rotolo, Rick Ramirez, Mark Koester, Siok Leong, Lila Ghamsari, Gene Merutka, Barry J. Kappel
Journal: Cancer Research (2019)

Abstract Anti-apoptotic B cell lymphoma 2 (Bcl-2) family proteins are frequently overexpressed across a variety of tumors, resulting in tumor cell survival and resistance to therapy. Inhibition of the expression or activity of these survival factors is an attractive approach for cancer therapy. Activating transcription factor 5 (ATF5) regulates gene transcription of anti-apoptotic Bcl-2 family proteins in neural progenitor cells and a wide range of human cancer cells. Here, we describe ST101, a rationally designed, synthetic, D-amino acid, cell penetrating peptide therapeutic designed to disrupt the protein-protein interactions driving ATF5-regulated gene transcription. Exposure of HL60 promyelocytic leukemia cells and MCF7 breast adenocarcinoma cells to low micromolar concentration of ST101 resulted in a decrease in MCL-1, BCL-2 and BIRC5 (Survivin) mRNA expression at 4 and 24 hrs post exposure. Further, exposure to ST101 resulted in a dose-dependent loss of viability across a panel of human cancer cells, including MCF7, HL60, U251 glioblastoma, A375 melanoma, DU145 prostate cancer, and A549 lung adenocarcinoma, characterized by an increase in annexin V and PI staining by flow cytometry peaking 48 hrs post exposure, resulting in a median half maximal effective concentration (EC50) value of 4.0 micromolar. In contrast, normal human peripheral blood mononuclear cells and bone marrow mononuclear cells were resistant to ST101-mediated cell death, with &amp;gt;80 micromolar EC50 values. In mouse xenograft experiments, 25mg/kg ST101 administered three times per week for three weeks resulted in significant tumor regression in MCF7 and U251 subcutaneous tumors as well as tumor growth delay in HL60 subcutaneous tumors. Tumor growth remained significantly inhibited weeks after the last treatment in the MCF7 and U251 models. In summary, ST101 selectively kills cancer cell lines by decreasing BCL-2 family gene expression, resulting in significant reductions in tumor growth in mouse models. Taken together, these data validate ST101 as a potent peptide therapeutic candidate for a variety of solid tumor and hematologic malignancies. Citation Format: Jim A. Rotolo, Rick Ramirez, Mark Koester, Siok Leong, Lila Ghamsari, Gene Merutka, Barry J. Kappel. Cell penetrating peptide, ST101, disrupts ATF5 regulation of anti-apoptotic Bcl-2 family proteins, resulting in induction of cancer cell death in vitro and tumor growth inhibition/regression in vivo [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 2050.
Expression pattern of death receptors FasR and DR3 on NK and T cells defines the complexity of tumor-immune system interplay in esophageal cancer
Authors: M. Snajdauf, Z. Strizova, J. Vachtenheim, J. Biskup, P. Taborska, D. Stakheev, R. Lischke, J. Bartunkova, D. Smrz
Journal: Annals of Oncology (2019)
Radiographic pulmonary vessel volume, lung function and airways disease in the Framingham Heart Study
Authors: Andrew J. Synn, Wenyuan Li, Raúl San José Estépar, Chunyi Zhang, George R. Washko, George T. O'Connor, Tetsuro Araki, Hiroto Hatabu, Alexander A. Bankier, Murray A. Mittleman, Mary B. Rice
Journal: European Respiratory Journal (2019)

Radiographic abnormalities of the pulmonary vessels, such as vascular pruning, are common in advanced airways disease, but it is unknown if pulmonary vascular volumes are related to measures of lung health and airways disease in healthier populations. In 2388 participants of the Framingham Heart Study computed tomography (CT) sub-study, we calculated total vessel volumes and the small vessel fraction using automated CT image analysis. We evaluated associations with measures of lung function, airflow obstruction on spirometry and emphysema on CT. We further tested if associations of vascular volumes with lung function were present among those with normal forced expiratory volume in 1 s and forced vital capacity. In fully adjusted linear and logistic models, we found that lower total and small vessel volumes were consistently associated with worse measures of lung health, including lower spirometric volumes, lower diffusing capacity and/or higher odds of airflow obstruction. For example, each standard deviation lower small vessel fraction (indicating more severe pruning) was associated with a 37% greater odds of obstruction (OR 1.37, 95% CI 1.11–1.71, p=0.004). A similar pattern was observed in the subset of participants with normal spirometry. Lower total and small vessel pulmonary vascular volumes were associated with poorer measures of lung health and/or greater odds of airflow obstruction in this cohort of generally healthy adults without high burdens of smoking or airways disease. Our findings suggest that quantitative CT assessment may detect subtle pulmonary vasculopathy that occurs in the setting of subclinical and early pulmonary and airways pathology.