tbuckley/cabot-search huggingface dataset:
Abstract 6468: Prognostic genomic alterations associated with recurrence after primary therapy for patients with luminal B breast cancer
Authors: Chun-Yu Liu, Ji-Lin Chen, Yi-Ting Yang, Yi-Fang Tsai, Ta-Chung Chao, Kien Thiam Tan, Wan-Lun Wang, Pei-Ju Lien, Shu-Jen Chen, Ling-Ming Tseng
Journal: Cancer Research (2020)

Abstract Purpose: Luminal type breast cancers account for the most common subtypes of breast cancers, among which luminal B subtype is relatively faster tumor growing and confers substantial risk of recurrence after primary treatment despite adjuvant endocrine therapy. Understanding the molecular alterations underlying the poorer survival outcome for luminal B tumors represents an unmet medical need. Experimental design: The archival samples of 16 recurrences within 5 years, 3 recurrences between 5-10 years and 24 non-recurrence tumor tissues from luminal B breast cancer patients were retrieved. Genomic alterations of these 43 breast cancer samples were detected using deep next-generation sequencing of a 440-gene panel. The mRNA levels of candidate genes in breast cancer patients were analyzed from The Cancer Genome Atlas (TCGA) database. Results: Overall, genomic alterations were found in 340 genes, including single nucleotide variants and copy number variation. Comparing to the non-recurrence tumors, NUP98 (31.3%), MAPK4 (18.8%), PTEN (18.8%), PER1 (18.8%) and TRIP11 (18.8%) showed higher population frequency in the recurrence tumors, and IGF2R (50.0%), PIM1 (45.8%) and ROS1 (37.5%) were dominate in the non-recurrence tumors. After a validation with the public clinical dataset, we identified three potential prognostic biomarkers, including NUP98, PER1, and TRIP11. We observed missense mutation or copy number deletion of NUP98, PER1 and TRIP11 in early recurrence tumors. Data from TCGA database exhibited patients with breast cancer harbored lower NUP98, PER1 and TRIP11 transcripts levels. Notably, lower NUP98, PER1 and TRIP11 expression levels correlated with worse recurrence-free survival in luminal B breast cancer. Interestingly, based on algorithm for visualization of protein interaction network, we found these 3 genes were all involved in androgen receptor signaling network. Conclusion: Our study identified NUP98, PER1, and TRIP11 which potentially served as biomarkers to predict recurrence in luminal B breast cancer. Further research is required to understand the association between genomic alterations and androgen receptor signaling as well as its clinical impact. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Yi-Ting Yang, Yi-Fang Tsai, Ta-Chung Chao, Kien Thiam Tan, Wan-Lun Wang, Pei-Ju Lien, Shu-Jen Chen, Ling-Ming Tseng. Prognostic genomic alterations associated with recurrence after primary therapy for patients with luminal B breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6468.
Abstract 1654: Highly multiplexed analysis of FFPE breast tissues using the codex technology
Authors: Nadezhda Nikulina, Oliver Braubach, Sayantani Basak, Maria Elena Gallina, Won-Mean Lee, Joseph Kim, Cassandra Hempel, Edek Williams, Olive Shang, Ben Cheung, Julia Kennedy-Darling
Journal: Cancer Research (2020)

Abstract Highly multiplexed imaging has emerged as a critical tool in understanding the complexities of the tumor microenvironment. This technology enables detection of tens of markers within the same tissue specimen, thereby allowing for key cell identification, quantification and spatial localization. These measurements can in turn provide insights into disease mechanisms and effective treatment modalities. In particular, with the high incidence of breast cancer and the need for early diagnosis and precise treatment regimens, highly multiplexed imaging could improve our understanding of this disease and provide the necessary data for improvements to patient health. Here, we demonstrate the development of a breast cancer specific CODEX panel for the measurement of more than 30 specific markers. The CODEX (Co-Detection by indEXing) platform enables detection of tens of markers within the same tissue specimen through a DNA-based tagging approach, whereby antibodies are labeled with specific oligonucleotide tags (barcodes) and dye-oligonucleotides (reporters) are iteratively hybridized and dehybridized across multiple cycles. This process is completely automated through the CODEX instrument in combination with existing fluorescent microscopes. Using FFPE Human breast cancer tissues at different stages as well as normal FFPE Human breast tissue utilizing the CODEX platform, data was generated for 30+ different biomarkers. This antibody panel was designed to detect cancer cells as well as non-malignant cells as part of tumor microenvironment to enable a better understanding of communication between the cells. The CODEX generated data was analyzed using the CODEX software suite to identify key cell types and analyze the spatial association between them. Upon analysis of data obtained, it was found that the biomarkers expression between the three samples were distinctly different. Using the CODEX technology, we were able to identify and classify key cell types and map the spatial localization of more than 20 key cell types. Citation Format: Nadezhda Nikulina, Oliver Braubach, Sayantani Basak, Maria Elena Gallina, Won-Mean Lee, Joseph Kim, Cassandra Hempel, Edek Williams, Olive Shang, Ben Cheung, Julia Kennedy-Darling. Highly multiplexed analysis of FFPE breast tissues using the codex technology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1654.
HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer
Authors: Ellen C. de Heer, Mathilde Jalving, Adrian L. Harris
Journal: Journal of Clinical Investigation (2020)

Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.
Abstract A75: Serine auxotrophy: A novel metabolic vulnerability of platinum-resistant ovarian cancer?
Authors: Tom Van Nyen, Joao A.G. Duarte, Matteo Rossi, Mélanie Planque, Esther Zaal, Ali Talebi, Stijn Moens, Guy Eelen, Hugo Horlings, Johan Swinnen, Celia Berkers, Peter Carmeliet, Reuven Agami, Sarah-Maria Fendt, Diether Lambrechts, Daniela Annibali, Frederic Amant
Journal: Clinical Cancer Research (2020)

Abstract Ovarian cancer accounts for the highest number of gynecologic-associated deaths in the developed world, and resistance to platinum-based therapy represents a major clinical and societal challenge in patients’ management. Since metabolism is intertwined with signaling pathways controlling cell death, we aimed to investigate to what extent metabolic adaptations could contribute to the development of the resistant phenotype. By performing isotope-labeled 13C-glucose tracer analysis in vitro, we found that, when they become resistant to platinum, ovarian cancer cells stop to synthetize serine and are characterized by significantly lower intracellular levels of this amino acid compared to sensitive cells. However, serine is required for cellular growth and survival, and resistant cells increase its uptake from the medium, becoming exquisitely vulnerable to serine starvation. We showed that, although resistant cells accumulate DNA damage upon platinum treatment, they have a higher capacity of repairing it because of increased poly(ADP)-ribose polymerase (PARP) activity, compared to the sensitive ones. Since PARP enzymes are major oxidized nicotinamide adenine dinucleotide (NAD+)-consuming enzymes, we collected evidence that serine synthesis downregulation, as a consequence of central carbon metabolic reshuffling, provides resistant cells with the advantage of sparing NAD+, thus sustaining PARP activation and allowing a more efficient DNA repair. We confirmed that downregulation of serine synthesis is a peculiar trait of resistant tumors also in vivo, using patient-derived xenografts (PDX) ovarian cancer models subjected to serine/glycine free diet. Moreover, analysis of The Cancer Genome Atlas Consortium (TCGA) ovarian cancer dataset revealed that tumors from platinum-resistant patients are characterized by a downregulation of serine biosynthetic enzymes, suggesting that serine auxotrophy could represent a novel and exploitable vulnerability of platinum-resistant ovarian cancers. Citation Format: Tom Van Nyen, Joao A.G. Duarte, Matteo Rossi, Mélanie Planque, Esther Zaal, Ali Talebi, Stijn Moens, Guy Eelen, Hugo Horlings, Johan Swinnen, Celia Berkers, Peter Carmeliet, Reuven Agami, Sarah-Maria Fendt, Diether Lambrechts, Daniela Annibali, Frederic Amant. Serine auxotrophy: A novel metabolic vulnerability of platinum-resistant ovarian cancer? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A75.
Abstract 5368: A multiparameter assay for HER2 protein detection on circulating tumor cells in non-small cell lung cancer
Authors: Edward Lo, Daniel Campton, Lillian Costandy, Heather Itamoto, Ryan Huston, Braden Gardner, Steve Reese, Arturo Ramirez, Eric P. Kaldjian, Tad George, I-Ming Wang, Steven Pirie-Shepherd
Journal: Cancer Research (2020)

Abstract Lung cancer biopsy can be difficult to perform successfully; it has a 30% adverse event risk and often provides insufficient material to test. Therefore, a liquid biopsy method to analyze the tumor is advantageous. Analysis of circulating tumor cells (CTCs) by multiparameter immunofluorescence (IF) microscopy allows non-invasive characterization of cancer cell biomarker expression. HER2 is a well-known therapeutic target in breast cancer and studies have shown that HER2 status on CTCs may provide prognostic information about response to anti-HER2 therapies. Less is understood about its frequency and clinical importance in non-small cell lung cancer (NSCLC). The RareCyte platform is uniquely suited for CTC identification and phenotypic characterization with a sensitive, accurate, simple and repeatable workflow from blood collection to CTC characterization and single-cell isolation. We developed an assay for detecting HER2 expression on lung CTCs using the RareCyte platform and validated the assay on model CTC spike-in samples with high (BT-474), medium (MDA-MB-453), low (H1650 and OVCAR-3) and absent (MDA-MB-468) HER2 protein levels. Blood was processed to slides using the AccuCyte Sample Preparation System and stained with anti-HER2 together with the RarePlex Kit for CTC identification (nuclear dye, anti-CD45 to exclude WBC, and anti-cytokeratin/EpCAM for CTCs). The spike-in samples showed the expected trend in per-cell HER2 mean fluorescence intensity values. The percentage of HER2-positive cells was &amp;gt; 90% for the HER2-high, medium and low cell lines, and &amp;lt; 5% for the HER2-negative cell line. The assay was applied to 10 advanced stage (III or IV) post-treatment NSCLC patient samples. At least 1 CTC was found in 6 samples (range 0-2043) and HER2 expression was confirmed in 5 out of the 6 samples, indicating this assay is useful for characterizing HER2 expression in CTCs in NSCLC. Citation Format: Edward Lo, Daniel Campton, Lillian Costandy, Heather Itamoto, Ryan Huston, Braden Gardner, Steve Reese, Arturo Ramirez, Eric P. Kaldjian, Tad George, I-Ming Wang, Steven Pirie-Shepherd. A multiparameter assay for HER2 protein detection on circulating tumor cells in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5368.
OP0083 Long-term use of the fully human anti-tnf antibody adalimumab (d2e7) in dmard-refractory rheumatoid arthritis
Authors: M Schattenkirchner, R Rau, LB Van de Putte, I Vallbracht, G Herborn, EJ Kroot, PL Van Riel, R Dressler, D Compagnone, H Kupper
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To evaluate the long-term efficacy and safety of the fully human anti-TNF antibody adalimumab (D2E7) given by the s.c. route to patients with active rheumatoid arthritis. <h3>Methods</h3> 24 patients with active rheumatoid arthritis who had previously failed a mean of 3.5 DMARDs were included in this 12-week randomised double blind, placebo-controlled study (DE004), and continued thereafter in an open label part of the study for up to two years on adalimumab. Initially, patients were assigned to either 0.5 mg/kg adalimumab s.c. weekly (18 patients) or placebo (6 patients). 22 patients entered the open-label part of the study: 15 patients who achieved EULAR response continued their previous adalimumab treatment schedule (0.5 mg/kg weekly), 2 patients who did not achieve a EULAR response at week 8 increased their adalimumab dose to 1 mg/kg weekly, and 5 patients previously on placebo received 1 mg/kg adalimumab s.c. weekly. Patient characteristics at baseline: 60 years mean age, 10 years mean RA duration, 5.35 mean Disease Activity Score (DAS). <h3>Results</h3> The overall efficacy results for the open label period of 24 months are summarised in the Table 1 below. Adverse events were well matched between the adalimumab treatment arm and placebo during the placebo-controlled period. After two years of treatment 14 patients were still receiving study drug. Reasons for drop out were lack of efficacy (4 pts), adverse events (3 pts), death (1 pt on placebo, 1 on adalimumab, both myocardial infarction), and protocol violation (1 pt). <h3>Conclusion</h3> Repeated weekly s.c. injections of a dose of 0.5 mg/kg or 1 mg/kg adalimumab (D2E7) given to patients with active rheumatoid arthritis over a period of two years were efficacious and well tolerated.
Men, trans/masculine, and non-binary people negotiating conception: Normative resistance and inventive pragmatism
Authors: Damien W. Riggs, Carla A. Pfeffer, Ruth Pearce, Sally Hines, Francis Ray White
Journal: International Journal of Transgender Health (2020)

Background Growing numbers of men, trans/masculine, and non-binary people are undertaking pregnancies, yet relatively little is known about the experiences of this diverse population in regard to conception.Aims This study sought to examine men's, trans/masculine, and non-binary people's experiences of pregnancy, including conception.Methods Interviews were conducted with 51 men, trans/masculine, and non-binary people who were gestational parents living in Australia, Canada, the European Union (including the United Kingdom), and the United States. Thematic analysis was undertaken, focusing on accounts of conception. Pfeffer's conceptual frameworks of normative resistance and inventive pragmatism were used as an analytic tool.Results Themes developed focused on: 1) choosing a clinic donor, 2) kinship with donors, 3) conceiving via intercourse with a partner, 4) negotiating receipt of donor sperm, 5) challenges associated with known donors, 6) challenges associated with fertility clinics, and 7) experiences of conception.Discussion The forms of normative resistance and inventive pragmatism identified suggest that men, trans/masculine, and non-binary people who are gestational parents seek to normalize their experiences of conception, while also acknowledging the specific challenges they face.
Abstract 2102: Interpretable machine learning for perturbation biology
Authors: Judy Shen, Bo Yuan, Augustin Luna, Anil Korkut, Debora Marks, John Ingraham, Chris Sander
Journal: Cancer Research (2020)

Abstract Systematic perturbation of cells followed by comprehensive measurements of molecular and phenotypic responses provides an informative data resource for constructing computational models of cell biology. Models that generalize well beyond training data can be used to identify combinatorial perturbations of potential therapeutic interest. Major challenges for machine learning on large biological datasets are to find global optima in an enormously complex multi-dimensional solution space and to mechanistically interpret the solutions. To address these challenges, we introduce a hybrid approach that combines explicit mathematical models of dynamic cell biological processes with a machine learning framework, implemented in Tensorflow. We tested the modeling framework on a perturbation-response dataset for a melanoma cell line after drug treatments. The models can be efficiently trained to accurately describe cellular behavior, as tested by cross-validation. Even though completely data-driven and independent of prior knowledge, the resulting de novo network models recapitulate known interactions. The main predictive application of our work is the identification of combinatorial candidates for cancer therapy. This approach is readily applicable to a wide range of kinetic models of cell biology. Citation Format: Judy Shen, Bo Yuan, Augustin Luna, Anil Korkut, Debora Marks, John Ingraham, Chris Sander. Interpretable machine learning for perturbation biology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2102.
Initial Invasive Versus Conservative Management of Stable Ischemic Heart Disease in Patients With a History of Heart Failure or Left Ventricular Dysfunction
Authors: Renato D. Lopes, Karen P. Alexander, Susanna R. Stevens, Harmony R. Reynolds, Gregg W. Stone, Ileana L. Piña, Frank W. Rockhold, Ahmed Elghamaz, Jose Luis Lopez-Sendon, Pedro S. Farsky, Alexander M. Chernyavskiy, Ariel Diaz, Denis Phaneuf, Mark A. De Belder, Yi-tong Ma, Luis A. Guzman, Michel Khouri, Alessandro Sionis, Derek J. Hausenloy, Rolf Doerr, Joseph B. Selvanayagam, Aldo Pietro Maggioni, Judith S. Hochman, David J. Maron
Journal: Circulation (2020)

Background: Whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in the setting of a history of heart failure (HF) or left ventricular dysfunction (LVD) when ejection fraction is ≥35% but &lt;45% is unknown. Methods: Among 5179 participants randomized into ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), all of whom had left ventricular ejection fraction (LVEF) ≥35%, we compared cardiovascular outcomes by treatment strategy in participants with a history of HF/LVD at baseline versus those without HF/LVD. Median follow-up was 3.2 years. Results: There were 398 (7.7%) participants with HF/LVD at baseline, of whom 177 had HF/LVEF &gt;45%, 28 HF/LVEF 35% to 45%, and 193 LVEF 35% to 45% but no history of HF. HF/LVD was associated with more comorbidities at baseline, particularly previous myocardial infarction, stroke, and hypertension. Compared with patients without HF/LVD, participants with HF/LVD were more likely to experience a primary outcome composite of cardiovascular death, nonfatal myocardial infarction, or hospitalization for unstable angina, HF, or resuscitated cardiac arrest (4-year cumulative incidence rate, 22.7% versus 13.8%; cardiovascular death or myocardial infarction, 19.7% versus 12.3%; and all-cause death or HF, 15.0% versus 6.9%). Participants with HF/LVD randomized to the invasive versus conservative strategy had a lower rate of the primary outcome (17.2% versus 29.3%; difference in 4-year event rate, −12.1% [95% CI, −22.6 to −1.6%]), whereas those without HF/LVD did not (13.0% versus 14.6%; difference in 4-year event rate, −1.6% [95% CI, −3.8% to 0.7%]; P interaction = 0.055). A similar differential effect was seen for the primary outcome, all-cause mortality, and cardiovascular mortality when invasive versus conservative strategy–associated outcomes were analyzed with LVEF as a continuous variable for patients with and without previous HF. Conclusions: ISCHEMIA participants with stable ischemic heart disease and at least moderate ischemia with a history of HF or LVD were at increased risk for the primary outcome. In the small, high-risk subgroup with HF and LVEF 35% to 45%, an initial invasive approach was associated with better event-free survival. This result should be considered hypothesis-generating. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01471522.