tbuckley/cabot-search huggingface dataset:
Abstract 3908: The combination of NVP-BEZ235 &amp; endostatin exerts synergistic anticancer activity against triple-negative breast cancer in vitro and in vivo
Authors: Xiaoshan Wang, Xiao Zhang, Fanghua Li
Journal: Cancer Research (2019)

Abstract Background: Triple-negative breast cancer(TNBC) take up 15% of invasive breast cancer. TNBC has no effective molecular targets &amp; unfavourable prognosis. We investigated the effects of NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, a combine with or not an angiogenesis inhibitor Endostatin in the orthotopic TNBC model &amp; explored its anti-tumor &amp; anti-angiogenesis mechanisms. Material &amp; Methods: Assess sensitivity of the cells to the drug by MTT assays.Orthotopic xenografts were performed for tumor growth and survival studies. Additionally, Immunohistochemistry for VEGF and MVD(CD34) was performed using the EnVision/HRP technique,Serum VEGF was detected by ELISA method. Results: BEZ235 effectively inhibited cell proliferation in vitro &amp; provided additive effects when combine with Endostatin.Treatment with BEZ235 &amp; Endostatin resulted in inhibition of tumor growth &amp; prolongation of survival time of tumor-bearing mice in vivo.Immunohistochemical analysis revealed that intratumoral proliferation &amp; angiogenesis was significantly suppressed. Furthermore, Changing of the number of Serum VEGF support the finding of angiogenesis inhibition too. Conclusion: Our findings suggest that BEZ235 exerts antitumor effects against TNBC &amp; enhances effects of Endostatin through inhibition of cell proliferation &amp; tumor angiogenesis. This approach may represent a promising combination targeted therapy for TNBC treatment. Note: This abstract was not presented at the meeting. Citation Format: Xiaoshan Wang, Xiao Zhang, Fanghua Li. The combination of NVP-BEZ235 &amp; endostatin exerts synergistic anticancer activity against triple-negative breast cancer in vitro and 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 3908.
Abstract 4630: <i>In vivo</i> characterization of the Duffy antigen receptor for chemokines (DARC/ACKR1) in breast cancer tumor progression
Authors: Rachel N. Martini, Brittany D. Jenkins, Lisa A. Newman, Nancy Manley, Melissa B. Davis
Journal: Cancer Research (2019)

Abstract In studies of the tumor microenvironment (TME), factors that influence immune cell infiltration are of great interest, as these populations can influence disease prognosis, and potential treatment for patients. Through in silico analysis of TCGA breast cancer (BC) cohort data, we have identified the Duffy antigen receptor for chemokine/atypical chemokine receptor 1 (DARC/ACKR1) as a potential driver of immune cell infiltration in the BC TME. DARC/ACKR1 is an atypical chemokine receptor that modulates levels of chemokine both in circulation through expression on red blood cells, and participates in chemokine transcytosis in tissues through expression on both post-capillary venules of endothelial cells and epithelial cells. As chemokines establish gradients to recruit specific immune cell types, we hypothesize that the function of DARC/ACKR1 in chemokine level modulation also influences tumor-associated immune cell levels. In the TCGA BC cohort, we observe a strongly positive and significant correlation between DARC/ACKR1 expression and total number of tumor-associated leukocytes, specifically populations of B cells, T cell, monocytes and macrophages. To further characterize the role of DARC/ACKR1 in vivo, we have established a novel DARC knock-out BC transgenic mouse model to study DARC/ACKR1 in the BC TME. To develop our target experimental mice, Ackr1-/- female mice were crossed with Ackr1 +/-; C3(1)Tag +/0 to generate the target Ackr1 -/-; C3(1)Tag +/0 experimental mice. Experimental mice and the littermate controls were aged to 3.5 months, at which point they were euthanized. Blood was collected from the mice to characterize the circulating chemokine profile. Mammary glands containing tumors were fixed and paraffin embedded, followed by IHC and immunofluorescent staining for expression of DARC/ACKR1, target chemokines, immune cells, epithelial cells and endothelial cells. The remaining glands were dissociated, followed by fluorescent-activating cell sorting analysis (FACS) to quantify abundance of immune cells in the gland. Using these methods, we have defined the circulating chemokine profile alongside patterns of immune cell infiltration in our target DARC/ACKR1 knockout BC mice compared to littermate controls in mouse mammary tumors. Citation Format: Rachel N. Martini, Brittany D. Jenkins, Lisa A. Newman, Nancy Manley, Melissa B. Davis. In vivo characterization of the Duffy antigen receptor for chemokines (DARC/ACKR1) in breast cancer tumor progression [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 4630.
Clinical outcomes with unfractionated heparin monitored by anti‐factor Xa vs. activated partial Thromboplastin time
Authors: James C. Coons, Carlo J. Iasella, Megan Thornberg, Mary Grace Fitzmaurice, Kimberly Goehring, Lindsay Jablonski, Dominic Leader, Abby Meyer, Hangil Seo, Neal J. Benedict, Roy E. Smith
Journal: American Journal of Hematology (2019)

Anti-factor Xa (anti-Xa) monitoring of unfractionated heparin (UFH) is associated with less time to achieve therapeutic anticoagulation compared to the activated partial thromboplastin time (aPTT). However, it is unknown whether clinical outcomes differ between these methods of monitoring. The aim of this research was to compare the rate of venous thrombosis and bleeding events in patients that received UFH monitored by anti-Xa compared to the aPTT. A retrospective review of electronic health records identified adult patients that received UFH given intravenously (IV) for ≥2 days, with either anti-Xa or aPTT monitoring at an academic tertiary care hospital. This was a pre/post study design conducted between January 1 to December 30, 2014 (aPTT), and January 1 to December 30, 2016 (anti-Xa). All UFH adjustments were based on institutional nomograms. The primary outcome was venous thrombosis and the secondary outcome was bleeding, both of which occurred between UFH administration and discharge from the index hospitalization. A total of 2500 patients were in the anti-Xa group and 2847 patients aPTT group. Venous thrombosis occurred in 10.2% vs 10.8% of patients in the anti-Xa and aPTT groups, respectively (P = .49). Bleeding occurred in 33.7% vs 33.6% of patients in the anti-Xa and aPTT groups, respectively (P = .94). Anti-Xa monitoring was not an independent predictor of either outcome in multivariate logistic regression analyses. Our study found no difference in clinical outcomes between anti-Xa and aPTT-based monitoring of UFH IV.
Abstract LB-002: SQ3370 enhances the safety of chemotherapeutics via local activation therapy
Authors: Nathan A. Yee, Sangeetha Srinivasan, Maksim Royzen, Jose M. Mejia Oneto
Journal: Cancer Research (2019)

Abstract With systemic chemotherapy, only 1-2% of the administered dose actually reaches a localized tumor, while the remaining leads to adverse off-target toxicities, including immunosuppression. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our patented approach (SQ3370) consists of: (1) SQL70 - a drug-activating biomaterial carrying no payload (2) SQP33 - a chemically-modified prodrug of doxorubicin (Dox) with attenuated activity. SQL70 is injected at the tumor site followed by SQP33 administered systemically. The prodrug first concentrates to the biomaterial at the tumor site due to their complementary chemical reactivities. The active drug is then spontaneously released over multiple days, providing sustained local delivery directly to the tumor region while reducing systemic side effects. Previously, we have shown that the greater safety of SQP33 allows it to be given at over 38 times the dose of standard Dox in SQL70-injected mice. Pharmacokinetic and biodistribution studies in SQ3370-treated rodents and dogs show that SQP33 disappears from plasma within the first hour of administration, likely due to the rapid concentration to SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to activated Dox. These studies also indicate that a single injection of SQL70 can activate multiple doses of SQP33, maximizing the local therapeutic index. Recent studies demonstrate that SQ3370 treatment enhances therapeutic response and survival in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 slowed tumor progression in 8/10 mice, showing improved efficacy compared to standard Dox or anti-PD-1 therapy. In mice bearing dual tumors, with one tumor site injected locally with SQL70, we observed that SQP33 can induce a response in both primary and secondary tumors, suggestive of an anti-tumor immune activation effect. Furthermore, we found that SQ3370 synergizes with anti-PD-1, expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy. Collectively, our results demonstrate that SQ3370 enables delivery of cytotoxic drugs to a target site while limiting exposure in off-target tissues in small and large animals, leading to improvements in both safety and efficacy. Citation Format: Nathan A. Yee, Sangeetha Srinivasan, Maksim Royzen, Jose M. Mejia Oneto. SQ3370 enhances the safety of chemotherapeutics via local activation therapy [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 LB-002.
Real World Data (RWD) of patients with chemorefractory metastatic colorectal cancer treated with trifluridine/tipiracil (TAS-102): clinical benefit from a Spanish single institution
Authors: A. Sánchez-Camacho, D. Herrero Rivera, I. Carrasco, M. Limón, J. Jimenez, M. Benavent, I. Gallego Jimenez, J. Martínez
Journal: Annals of Oncology (2019)
Abstract 1497: Identification of discrepancy between CTLA4 expression and CTLA4 activation in gastric cancer
Authors: Yingyan Yu
Journal: Cancer Research (2019)

Abstract Objective: Recently, immune checkpoints blockers showed higher anti-tumor activity for advanced gastric cancer (GC). The purpose of the study is to find out biomarkers related to anti-CTLA4 therapy. Materials and Methods: Datasets of GEO, TCGA and GESA were extracted. Differential expression of CTLA4 between cancer tissues and normal mucosa, enrichment of WT (wild type) vs CTLA4_KO (knockout) upregulated gene set and clinical significance were analyzed. The expression of CTLA4,CD3 and granzyme A (GZMA) were validated on 30 cases of Chinese GC. MSI marker MLH1 and EBV marker EBER were examined on 30 cases of Chinese GC by immunohistochemistry and in situ hybridization. Results: CTLA4 was up-regulated in GC tissue relative to normal mucosa in datasets of GSE27342 (fold change=1.586, P&amp;lt;0.001) and GSE63089 (fold change=1.365, P&amp;lt;0.001). Increased CTLA4 expression was positively related to CTLA4 activation. EBV-associated GC (EBVaGC) and microsatellite instability GC (MSIGC) disclosed higher CTLA4 levels than other GCs. Genomic stability GC (GSGC) also showed higher enrichment score of CTLA4 activation. CTLA4 activation resulted in shorter overall survival in GC. The expression level of CTLA4 was well correlated to GZMA (R=0.701, P&amp;lt;0.001) and CD3 (R=0.750, P&amp;lt;0.001). Conclusions: GSGC was firstly identified as the potential GC subtypes responsive to anti-CTLA4 treatment. Note: This abstract was not presented at the meeting. Citation Format: Yingyan Yu. Identification of discrepancy between CTLA4 expression and CTLA4 activation in gastric 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 1497.
Abstract 205: BBI-608 enhances the activity of chemoradiotherapy in colorectal cancer pre-clinical models
Authors: Ganji Purnachandra Nagaraju, Rajitha Balney, Shipra R. Bethi, Sneha Govardhanagiri, Gregory B. Lesinski B. Lesinski, Bassel F. El-Rayes
Journal: Cancer Research (2019)

Abstract Background: Chemoradiotherapy is a standard treatment modality for early stage rectal cancer (CRC). The pathologic complete response rate after chemoradiation in CRC remains low at 15%. Given the potential for BBI608 to elicit effects on multiple oncogenic cellular pathways, we hypothesized that BBI608 can sensitize colorectal cell lines to the effects of chemoradiotherapy. The aim of this study was to evaluate if BBI-608 enhances the response of chemoradiotherapy against CRC. Methods: The combined effects of BBI-608 and chemoradiotherapy [5-FU + ionizing radiation (IR)] were evaluated in CRC cell lines (HCT 116 and HT-29) using Br-dU cell proliferation and clonogenic assays. Effects on the expression of DNA damage and repair (pATM, pATR, Rad51 and γ-H2AX) molecules and angiogenesis (pSTAT-3 and VEGF) pathways were examined by Western blot. Egg CAM assay was also performed to evaluate effects of the drugs on angiogenesis (quantification was performed by AngioQuant software). The in vivo efficacy of BBI-608 alone or combined with 5-FU + IR, was evaluated in nude mice bearing subcutaneous human HCT116 xenograft tumors Results: The combination of BBI-608 and chemoradiotherapy significantly decreased cell proliferation (p&amp;lt;0.001), colony formation (p&amp;lt;0.001) and inhibited angiogenesis (p&amp;lt;0.001) in CRC cell lines as compared to chemoradiotherapy. BBI-608 decreased angiogenesis as determined by both matrigel plug and egg CAM assays. Immunoblot analysis indicated BBI-608 and chemoradiotherapy also decreased expression of pSTAT-3, MDM2, Rad51 and VEGF while increasing pATM, γ-H2AX and p53, in comparison to chemoradiotherapy alone. In animal models, combined therapy with BBI-608 and 5-FU + IR led to significant inhibition of longitudinal tumor growth as compared to chemoradiotherapy alone (p&amp;lt;0.001). No overt signs of systemic toxicity were evident and animals showed no loss of body weight in any of the treatment groups, indicating the combination was well-tolerated. Conclusion: These observations provide preclinical proof-of-principle data that BBI-608 can enhance the anti-tumor effects of chemoradiotherapy. BBI608 plus chemoradiotherapy is a rational approach for potential future development in early stage rectal cancer. Citation Format: Ganji Purnachandra Nagaraju, Rajitha Balney, Shipra R. Bethi, Sneha Govardhanagiri, Gregory B. Lesinski B. Lesinski, Bassel F. El-Rayes. BBI-608 enhances the activity of chemoradiotherapy in colorectal cancer pre-clinical models [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 205.
Effects of obesity on overall survival (OS) of patients with acute myeloid leukemia (AML).
Authors: Prajwal Dhakal, Elizabeth Lyden, Andrea Lee, Joel Michalski, Zaid S. Al-Kadhimi, Lori J. Maness, Krishna Gundabolu, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2019)

e18510 Background: The relationship between obesity and prognosis of AML has not been established. Our retrospective study aimed to determine the effect of obesity on OS of AML. Methods: AML patients diagnosed from 2000-2016 at University of Nebraska Medical Center were included. Body mass index (BMI) at the time of AML diagnosis was divided into 3 groups: normal (18.5≤25 kg/m2) or underweight (&lt;18.5 kg/m2); over-weight (25-30 kg/m2); and obese (≥30 kg/m2). Chi-square test, Kruskal-Wallis test and ANOVA were used to look at the association of different BMI groups with other patient characteristics. Mann-Whitney test was used for pairwise comparisons of hematopoietic cell transplant (HCT) co-morbidity index and Bonferroni correction was used to adjust p-values. OS, defined as time from diagnosis to death from any cause, was determined by Kaplan-Meier method and comparisons were done using log-rank test. Cox Regression was performed to detect survival effect of BMI (as continuous variable). P&lt;0.05 was considered statistically significant. Results: A total of 314 patients were included in the study (Table): 46% were female, 35% had adverse cytogenetics, 15% had FLT3-ITD mutation, 68% received intensive chemotherapy and 30% underwent HCT. 38% of total patients were obese. Baseline characteristics were similar in all 3 BMI groups except co-morbidity index (p=0.04). OS for normal/underweight, overweight and obese groups at 1 year was 85%, 92%, and 94% respectively (p=0.84). BMI, as a continuous variable, was not a significant risk factor for death (HR 1.00, 95% CI 0.98-1.03). Conclusions: Obese patients, compared to non-obese patients, did not differ in baseline characteristics other than increased comorbidity burden. Obesity, when adjusted for other characteristics, did not have any effect on OS of patients with AML. Patient characteristics. [Table: see text]
Preventing Maternal Deaths
Authors: Bridget Kuehn
Journal: JAMA (2019)

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Long-term effects of ibrutinib on blood pressure in patients with chronic lymphocytic leukemia (CLL).
Authors: Jade Jones, Binsah George, Christine B Peterson, Jan Andreas Burger, Nitin Jain, William G. Wierda, Michael J. Keating, Jean-Bernard Durand, Alessandra Ferrajoli
Journal: Journal of Clinical Oncology (2019)

e19009 Background: Ibrutinb is approved for treatment of CLL. Hypertension (HTN) has been reported as a side effect of ibrutinib in 1-23% of patients. We previously reported HTN in CLL patients after 6 months of treatment with ibrutinib. In this study we describe the effects of long-term treatment with ibrutinib on blood pressure (BP). Methods: We performed a retrospective study, evaluating 150 CLL patients on ibrutinib-based clinical trials from 2010 to 2015. Patient demographics, co-morbidities, tobacco use, anti-HTN therapy were recorded. BP was evaluated at baseline and sequentially for up to 5 yrs. New onset HTN was defined as systolic BP (SBP) of ≥ 130 mmHg and/or diastolic BP (DBP) ≥ 80 on two separate visits with no prior HTN or anti-HTN therapy. An increase in baseline SBP by ≥10 and/or increase in DBP by ≥10 was considered significant regardless of the absolute BP. Univariate logistic regression analysis was performed to assess relationship of HTN risk factors and new HTN. Results: Patients’ median age was 65 yrs (68% male and 88% white). Median follow-up was 3 yrs. Pre-existing HTN was present in 44% of patients, 40% were on anti-HTN therapy prior to ibrutinib. New HTN developed in 65% of patients without prior diagnosis of HTN; 32 % of patients were started on anti-HTN therapy or received additional anti-HTN therapy. Of the patients who experienced an increase in BP, 33% experienced isolated systolic HTN. Median SBP was 130 at baseline, 132 at 1mo, 137 at 3mo, 135 at 6mo, 139 at 12mo, 138 at 3yrs, 144 at 5yrs (mean increase in SBP: 7.2, P &lt; 0.001). In patients whose SBP was &lt; 130 at baseline the median SBP was 119 at baseline, 122 at 1mo, 134 at 3mo, 130 at 6mo, 134 at 12mo, 135 at 3yrs and 141 at 5yrs (mean increase in SBP: 15.7, p &lt; 0.001). 74% of patients experienced and increase in SBP ≥10. New HTN on ibrutinib was not associated with: tobacco use, obesity, chronic kidney disease or obstructive sleep apnea (p &gt; 0.05). Conclusions: In this study we demonstrated a high rate of new HTN in patients on prolonged ibrutinib treatment. HTN in these patients is persistent, linear and independent of other risk factors. The increase in BP remained despite initiation of anti-HTN therapy. Additional studies are ongoing to define cardiovascular and renal complications associated with HTN in these patients.
Evaluation of the mimetic peptide APOE COG1410 in the viability, migration, and apoptosis of the intestinal cells IEC-18 after injuries by 5-FU
Authors: T. Pessoa, I. Carneiro, P. Aguiar, L. Vieira, R. Guerrant, M. Vitek, J. Abreu Junior, R. Oria
Journal: Annals of Oncology (2019)
Abstract 17283: Risk Score Identifies Patient With Diabetes and Multivessel Coronary Artery Disease Who Can Safely Defer Coronary Artery Bypass Surgery: An Analysis of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study
Authors: Andrew Perry, Matthew Chung, Eric Novak, Ronald Krone, David Brown
Journal: Circulation (2017)

Introduction: Current ACC/AHA guidelines provide a Class I recommendation that patients with diabetes and symptomatic multivessel coronary artery disease be treated with coronary artery bypass surg...