tbuckley/cabot-search huggingface dataset:
Abstract 3085: Steroid receptor co-activators regulate metabolic kinases to drive therapy resistant ER+ breast cancer
Authors: Thu Ha Truong, Elizabeth Benner, Kyla M. Hagen, Nuri A. Temiz, Carlos Perez Kerkvliet, Ying Wang, Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Thomas Pengo, Katrin P. Guillen, Bryan E. Welm, Sucheta Telang, Carol A. Lange, Julie H. Ostrander
Journal: Cancer Research (2021)

Abstract Recurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs are poorly proliferative and frequently exist as a minority population in therapy resistant tumors. Our objective is to define novel signaling pathways that govern therapy resistance in ER+ breast cancer. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genes PFKFB3 and PFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein-protein interactions with SRC-3. PFKFB4 knockdown inhibited in vivo emergence of circulating tumor cell (CTC) populations in ER+ mammary intraductal (MIND) xenografts. Application of PFKFB inhibitors in combination with ER targeted therapies blocked tumorsphere formation in multiple models of advanced breast cancer, including tamoxifen (TamR) and paclitaxel (TaxR) resistant models and ER+ patient-derived organoids (PDxO). Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cells that include CSCs and CTCs. Identifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance in ER+ breast cancer. Citation Format: Thu Ha Truong, Elizabeth Benner, Kyla M. Hagen, Nuri A. Temiz, Carlos Perez Kerkvliet, Ying Wang, Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Thomas Pengo, Katrin P. Guillen, Bryan E. Welm, Sucheta Telang, Carol A. Lange, Julie H. Ostrander. Steroid receptor co-activators regulate metabolic kinases to drive therapy resistant ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3085.
Abstract 9486: Different Influences of Hematocrit on the Results of Two Point-of-Care Platelet Function Tests, the VerifyNow Assay and Multiple Electrode Platelet Aggregometry
Authors: Yun Gi Kim, Jung-Won Suh, Jin Joo Park, Il-Young Oh, Chang-Hwan Yoon, Young-Seok Cho, Tae-Jin Youn, In-Ho Chae, Dong-Ju Choi
Journal: Circulation (2014)

Introduction: Previous studies have reported a considerable association between the VerifyNow (Accumetrics, San Diego, CA, USA) P2Y12 assay results and hematocrit. No reports, however, have described an association between the multiple electrode platelet aggregometry (MEA; Dynabyte, Munich, Germany) adenosine diphosphate (ADP) assay results and hematocrit. Methods: A total of 462 consecutive patients who were undergoing percutaneous coronary intervention were enrolled. Platelet function was evaluated with both the VerifyNow P2Y12 and MEA ADP assays. Results: Anemic patients (n=152, 32.9%) demonstrated a significantly higher rate of cardiac death, myocardial infarction, and stroke (5.3% vs. 2.3%, p=0.046) during the follow-up (median: 18.8 months). Although the VerifyNow P2Y12 assay results demonstrated a significant inverse correlation with hematocrit (r=-0.409, p<0.001, Figure 1-A), there was no such correlation between the MEA ADP assay results and hematocrit (r=0.039, p=0.401, Figure 1-B). Anemic patie...
The expression of glutamate cysteine ligase (GCL) subunit in human non-small cell lung cancer xenografts
Authors: Yoshiyuki Abe, Masatake Nishi, Hiroyuki Hatanaka, Yasuyuki Ohnishi, Hitoshi Yamazaki, Hiroshi Kijima, Masato Nakamura
Journal: Cancer Research (2004)

530  Glutamatae cysteine ligase (GCL) is a key enzyme in glutathione (GSH) synthesis, and is thought to play a significant role in intracellular detoxification of anticancer drugs, especially of cisplatin (CDDP). The GCL is composed of a modifier subunit (GCLM) and a catalytic subunit (GCLC). It was unclear whether a subunit is an effective molecular target to relieve CDDP-resistance. We examined the gene expression of GCLM and GCLC in thirty-nine xenografts of human non-small cell lung cancer by real time-PCR assay. Drug sensitivity to CDDP was evaluated in the nine xenografts by the in vivo drug sensitivity test. There was association between the expression of GCLM and GCLC mRNA in each xenograft (Fisher’s test, p
Abstract 1725: Short-term administration of high dose mIL-2/CD25 fusion protein elicits CD8+ T cell-driven anti-tumor immunity and memory
Authors: Kathryn LaPorte, Rosmely Hernandez, Thomas Malek
Journal: Cancer Research (2021)

Abstract Recombinant IL-2 (rIL-2) promotes the differentiation, proliferation, and survival of antigen-activated T cells and induces potent anti-tumor activity. High dose (HD) rIL-2 broadly targets T effector (Teff) and NK cells. However, rIL-2 cancer therapy requires long-term infusions of high doses due to its short half-life and is associated with severe toxicities which limit efficacy. To circumvent these limitations, our lab has developed and is testing a new IL-2-based biologic, mIL-2/CD25, which can be used at high doses to promote anti-tumor immunity. mIL-2/CD25 is a fusion protein (FP) composed of mouse IL-2 fused to the mouse CD25 extracellular domain via a non-cleavable glycine-serine linker with selectivity toward the high affinity IL-2R. This FP has a much longer half-life (16 hr) than rIL-2 (15 min). At a low dose, mIL-2/CD25 selectively expands Tregs, but at a HD, Teff cells are also engaged. These properties allow for HD FP to readily expand activated endogenous tumor-reactive Teff cells, but not memory-phenotypic CD8+ T cells and NK cells. In the current study, we tested the extent short-term HD FP therapy activated tumor-reactive Teff cells to elicit efficacious anti-tumor immunity responses despite Treg stimulation. HD FP prolonged survival in mice bearing B16.F10 melanoma, MC-38 colon adenocarcinoma, or CT26 colon carcinoma. In the CT26 model, a significant increase in both the number and the frequency of CD8+ T cells was detected in the tumor microenvironment (TME) of treated mice. FP-dependent Treg expansion was observed in secondary lymphoid tissues but not the TME. This therapeutic approach, therefore, led to a higher CD8+ Teff to Treg ratio specifically in the TME. After FP treatment, CD8+ T cells isolated from the TME expressed lower levels of TOX, PD-1, and LAG-3, suggesting that they were less exhausted. T cell depletion studies using anti-CD8 revealed that CD8+ T cells are the major driver of the FP-induced anti-tumor response. Rechallenge of animals that had previously cleared CT26 due to FP treatment led to successful tumor rejection, showing that the FP supported anti-tumor memory. These findings demonstrate that mIL-2/CD25 amplifies recently activated tumor-reactive CD8+ Teff cells to generate efficacious anti-tumor responses that limit Treg-dependent negative regulation in the TME and lead to anti-tumor memory. Citation Format: Kathryn LaPorte, Rosmely Hernandez, Thomas Malek. Short-term administration of high dose mIL-2/CD25 fusion protein elicits CD8+ T cell-driven anti-tumor immunity and memory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1725.
High-Intensity vs Low-Intensity Knowledge Translation and Performance Metrics in Patients With Rectal Cancer
Authors: Steven D. Wexner
Journal: JAMA Network Open (2021)

Marko Simunovic, MD; David Robert Urbach, MD; Christine Fahim, PhD; Mary Ann O’Brien, PhD; Craig C. Earle, MD; Melissa Brouwers, PhD; Evgenia Gatov, MPH; Vanja Grubac, MSc; Daniel McCormack, MSc; Nancy Baxter, MD
Abstract 2832: Targeted genomic landscape of metastases compared to primary tumors in non-small-cell lung cancer
Authors: Bing Chen, Gaochao Dong, Yingkuan Liang, Te Zhang, Junling Zhang, Shiqing Chen, Feng Jiang, Lin Xu
Journal: Cancer Research (2021)

Abstract The genomic landscape of primary non-small-cell lung cancer (NSCLC) has been well described. However, little is known about cohort genomic alterations (GA) landscape in NSCLC metastases, and how it compares with primary tumors in general. The genomic landscape of metastases may be important for clinical treatment and prognosis. In this retrospective study, 37 cases of surgically resected NSCLC were studied, of which 19 were non-metastatic NSCLC and 18 were metastatic NSCLC. Sixty formalin-fixed paraffin-embedded (FFPE) tissue samples from 37 NSCLC patients, including the primary lesion of non-metastatic NSCLC (Group A, N =19), the primary lesion of metastatic NSCLC (Group B, N =18), and lymph node lesions (Group C, N =23), were included to detect somatic mutations using a 1021-gene panel by next-generation sequencing (NGS). In this study, twenty-nine patients (78.4%) were male. Nineteen patients with lung adenocarcinoma (LUAD) and 18 with lung squamous cell carcinoma (LUSC) were included. In addition, there were significant differences between Groups A and B in stage T and stage N (P &amp;lt; 0.0001). Overall, EGFR (33.3% vs 15.8%) and TERT (16.7% vs 5.2%) were numerically more frequently mutated in metastases, but differences were not statistically significant. Moreover, we found that ARID1A may be closely related to metastasis in LUSC (P = 0.029). These data support the theory that primary and metastatic NSCLC encompass a uniform distribution of common genomic alterations tested by next-generation sequencing targeted panels. While ARID1A may be closely related to metastasis in LUSC. Citation Format: Bing Chen, Gaochao Dong, Yingkuan Liang, Te Zhang, Junling Zhang, Shiqing Chen, Feng Jiang, Lin Xu. Targeted genomic landscape of metastases compared to primary tumors in non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2832.
Error in Dates in Figures
Authors: Andrea Angeletti, Pietro Ravani, Gian Ghiggeri
Journal: JAMA Pediatrics (2021)

Robin Ortiz, MD; Rachel Kishton, MD; Laura Sinko, PhD, RN; Michelle Fingerman, MS; Diane Moreland, MS; Joanne Wood, MD, MSHP; Atheendar Venkataramani, MD, PhD
Abstract 403: The landscape of PD-L1 expression in lung cancer harboring EGFR mutations
Authors: Linlin Zhang, Fuyu Gong, Fanlu Meng, Xin Wang, DianSheng Zhong
Journal: Cancer Research (2021)

Abstract Background: Results from previous studies indicated that lung cancer patients harboring EGFR sensitizing mutations may receive unfavorable outcomes from immunotherapy. The present study aims to investigate the landscape of PD-L1 expression in lung cancer harboring EGFR mutations. Methods: Tissue samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for driver oncogene mutations and PD-L1 expression. Results: A total of 22143 lung cancer patients were selected, including 12278 (55.4%) male and 9865 (44.6%) female with a median age of 63. There are 9560 patients has the EGFR mutation, and the frequency of EGFR mutation is 43.2%. Among the EGFR mutation patients, 1602 patients have been collected tumor tissue, and the PD-L1 expression have been tested by FDA-approved SP263 and 22C3 antibodies. Among all the EGFR mutation cases assessed PD-L1 expression (n=1602), low PD-L1 expression levels (&amp;lt;1%) were more than half proportion with 56.5% (n=905), PD-L1 expression level of 1%-49% accounted for 31.2% (n=905), PD-L1 expression level of 50%-79% accounted for 9.1% (n=146), PD-L1 expression level of 80%-89% accounted for 1.8% (n=29), and PD-L1 expression level higher than 90% accounted for 1.4% (n=22). Conclusion: Our study supported that NSCLC patients harboring sensitizing oncogenic mutations may potentially benefit from anti-PD-1/L1 especially for those with positive indicators of immunotherapy with strong positive PD-L1 expression. Citation Format: Linlin Zhang, Fuyu Gong, Fanlu Meng, Xin Wang, DianSheng Zhong. The landscape of PD-L1 expression in lung cancer harboring EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 403.
Abstract LB248: Implantation factors assist in the growth of gynecologic tissues in ectopic locations
Authors: Jan Sunde, Derek O'Neil, Tiffany Katz, Morgan Wasickanin
Journal: Cancer Research (2021)

Abstract OBJECTIVE: Develop a model of endosalpingiosis and endometriosis to investigate the mechanisms which facilitate implantation of exfoliated cells in the peritoneum. BACKGROUND: Endosalpingiosis (ES) and endometriosis (EM) are the growth of tubal and endometrial epithelium respectively, outside of their site of origin and have been associated with ovarian cancer. Why this growth happens has not been elucidated since Sampson first proposed the concept of retrograde menstruation nearly 100 years ago. We hypothesized there is retrograde flow of uterine implantation factors which drive ectopic growth. To test this hypothesis, we developed a transgenic fluorescent murine model of ES and EM that successfully demonstrated peritoneal implantation in mice. Using the model, we explored possible influences on implantation. METHODS: tdTomato (tdT) transgenic fluorescent mice were used as donors to allow for visualization of tissues in recipient mice. A progesterone knockout (PKO) of the tdT mouse that blocks implantation factors was created by giving 0.1 mg/kg progesterone on postnatal days 2-10. Metestrus endometrium was induced hormonally in donor tdT and wild-type (WT) female C57BL/6J mice. The tdT oviductal cells and endometrium were then harvested for intraperitoneal injection into synchronized recipient WT mice, receiving minced endometrium alone, minced oviduct alone, or a combination of minced oviduct and WT endometrial tissue (for implantation factors) from non-treated or PKO tdT donors. Ectopic lesions were identified using fluorescence in-vivo imaging and UV light. RESULTS: PKO tdT oviduct had significantly reduced implantation (4 lesions/6 mice, p&amp;lt;0.02) compared to tdT oviduct without treatment (28 lesions/8 mice). Additionally, PKO tdT oviduct implantation (10 lesions/3 mice) may be restored when implanted with WT endometrium (p=0.07). Chi square was used to evaluate for statistical significance. ConclusionImplantation factors required for blastocyst implantation are crucial to initiate ectopic tissue growth. We have developed a novel mouse model of ectopic growth of gynecologic tissues which demonstrates that the removal of implantation factors from endometrium and oviduct reduces ectopic lesions. This model allows us to study the initial step of implantation of these lesions that could give rise to malignancies which will ultimately allow for the development of new prevention and treatment modalities. Citation Format: Jan Sunde, Derek O'Neil, Tiffany Katz, Morgan Wasickanin. Implantation factors assist in the growth of gynecologic tissues in ectopic locations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB248.
Abstract 17029: Plasma B-type Natriuretic Peptide Levels and the Risk of Death in Clinically-referred Patients With and Without Heart Failure
Authors: Michelle K York, Cassandra F Reynolds, Eric Farber-Eger, Quinn S Wells, Katherine N Bachmann, Meng Xu, Frank Harrell, Deepak K Gupta, Thomas J Wang
Journal: Circulation (2016)

Introduction: B-type natriuretic peptide (BNP) levels are an important predictor of mortality in heart failure (HF) patients. Less is known about the prognostic significance of BNP in clinically-re...
Traction-assisted endoscopic submucosal dissection of a duodenal gastrointestinal stromal tumor
Authors: Francisco Baldaque-Silva, Naining Wang, Ioannis Rouvelas, Masami Omae
Journal: Endoscopy (2021)

A 70-year-old woman with a gastric adenocarcinoma and a subepithelial lesion in the distal descending duodenum ([Fig. 1]) was referred to us. On endoscopic ultrasound (EUS), a 15-mm hypoechoic, regular, and homogeneous lesion engaging the muscularis propria was observed ([Fig. 2]). Histopathology analysis of the fine-needle biopsy showed a gastrointestinal stromal tumor (GIST) with a low proliferative index. After discussion in a multidisciplinary team conference and on patient consent, an endoscopic submucosal dissection (ESD) and gastrectomy were performed in the same session.
Management of cardiac fibrosis is the largest unmet medical need in heart failure
Authors: Javier Díez, Rudolf A de Boer
Journal: Cardiovascular Research (2021)

Cardiac fibrosis is a major driver associated with the growing burden of heart failure, especially in older people. However, integrating cardiac fibrosis in heart failure management is still an unmet medical need, which may be explained by its high tissue heterogeneity and clinical diversity, and, as a consequence, the very real limitations of its diagnosis and treatment. In this viewpoint article we summarize the challenges and requirements in the clinical management of cardiac fibrosis in heart failure patients.
Intraprostatic recurrences on PSMA PET/CT after prostate whole gland radiotherapy. Is histological confirmation necessary?
Authors: H.B. Luiting, M.L. Donswijk, T. Witteveen, E. Schaake, T.N. Boellaard, M.J. Roobol, P.J. Van Leeuwen
Journal: European Urology (2021)
Abstract 1525: Enhancing potency of antigen presenting cells via signal 2/3 mRNA engineering through Cell Squeeze® technology
Authors: Emrah Ilker Ozay, Paul Dunbar, Kelly Volk, Michael F. Maloney, Christian Yee, Mubeen Mosaheb, Christine Trumpfheller, Pablo Umana, Katherine J. Seidl, Howard Bernstein, Scott M. Loughhead
Journal: Cancer Research (2021)

Abstract Antigen-specific CD8+ T cells are critical effectors of the immune system that help limit persistence of tumors and virally infected cells. During priming, T cells integrate three signals which determine the magnitude and quality of response generated. Signal one is T cell receptor(TCR) and peptide-MHC (pMHC) engagement, which determines the specificity of the response.Signal two is cell surface costimulation by antigen presenting cells (APCs). Signal three is provided through the local cytokine milieu at the time of priming. Here, we use microfluidic CellSqueeze® technology to deliver mRNAs encoding antigen (signal 1), costimulatory molecules(signal 2), and chimeric membrane-tethered cytokines (signal 3) to the cytosol of human peripheral blood mononuclear cells (PBMCs), generating antigen presenting cells (APCs) with multiple enhanced functions. We demonstrate that microfluidic squeezing enables delivery and expression of single or multiple mRNAs encoding signal 1 (various antigens), signal 2 (CD70 orCD86) and/or signal 3 (membrane-tethered form of IL-2) by the major subsets of PBMCs (T cells, B cells, NK cells, and monocytes). While unsqueezed PBMCs showed no to minimal expression of signal 2 and no expression of signal 3 molecules, expression of delivered signal 2and 3 mRNAs in squeezed PBMCs could be observed on the cell surface for several days post squeeze delivery - a timeframe that could potentially support improved T cell priming. When these signal 2/3 molecules were delivered alone or in combination, antigen-specific CD8+ T cell responses could be increased as much as ten-fold compared to delivery of antigen alone.Therefore, microfluidic cell squeezing enables us to efficiently deliver mRNA antigens that have potential to generate multiple immune epitopes in an HLA agnostic manner. Moreover,multiplexing these antigens with signal 2/3 mRNAs enhances the antigen presenting potency ofSQZ APCs inducing stronger antigen-specific CD8+ T cell responses. The potential to deliver numerous materials simultaneously and engineer compound signals via mRNA could allow for applications for HLA-agnostic patient population in oncology and infectious disease areas. Citation Format: Emrah Ilker Ozay, Paul Dunbar, Kelly Volk, Michael F. Maloney, Christian Yee, Mubeen Mosaheb, Christine Trumpfheller, Pablo Umana, Katherine J. Seidl, Howard Bernstein, Scott M. Loughhead. Enhancing potency of antigen presenting cells via signal 2/3 mRNA engineering through Cell Squeeze® technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1525.
The prognostic value of histopathological nodal features in patients with pelvic lymph node metastases of prostate cancer after extended pelvic lymph node dissection
Authors: D. Meijer, R.H. Ettema, P.J. Van Leeuwen, H.G. Van Der Poel, N.H. Hendrikse, D.E. Oprea-Lager, E.M. Bekers, A.N. Vis
Journal: European Urology (2021)
Urinary Thromboxane B2 and Lethal Prostate Cancer in African American Men
Authors: Maeve Kiely, Ginger L Milne, Tsion Z Minas, Tiffany H Dorsey, Wei Tang, Cheryl J Smith, Francine Baker, Christopher A Loffredo, Clayton Yates, Michael B Cook, Stefan Ambs
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Thromboxane A2 (TXA2) is a platelet- and cyclooxygenase-derived eicosanoid that has been linked to metastasis. We investigated the role of TXA2 in the development of lethal prostate cancer in African American (AA) and European American (EA) men. Methods We measured urinary 11-dehydrothromboxane B2 (TXB2), a stable metabolite of TXA2, with mass spectrometry. Samples were obtained from 977 cases and 1022 controls at time of recruitment. We applied multivariable logistic and Cox regression modeling to examine associations of TXB2 with prostate cancer and patient survival. The median survival follow-up was 8.4 years, with 246 deaths among cases. Aspirin use was assessed with a questionnaire. Race was self-reported. Results Urinary TXB2 was inversely associated with aspirin use. High (&amp;gt;median) TXB2 was associated with prostate cancer in AA (adjusted odds ratio [OR] = 1.50, 95% confidence interval [CI] = 1.13 to 2.00) but not EA men (OR = 1.07, 95% CI = 0.82 to 1.40), suggesting upregulated TXA2 synthesis in AA men with prostate cancer. High TXB2 was positively associated with metastatic prostate cancer (OR = 2.60, 95% CI = 1.08 to 6.28) compared with low (≤median) TXB2. Furthermore, high TXB2 was also associated with all-cause (adjusted hazard ratio = 1.59, 95% CI = 1.06 to 2.40) and prostate cancer-specific mortality (hazard ratio = 4.74, 95% CI = 1.62 to 13.88) in AA men only. Conclusions We report a distinct association of TXB2 with prostate cancer outcomes in AA men. In this high-risk group of men, upregulation of TXA2 synthesis may promote metastasis and lethal disease. Our observation identifies a potential benefit of aspirin in preventing lethal prostate cancer through inhibition of TXA2 synthesis.