tbuckley/cabot-search huggingface dataset:
Abstract 2358: Porphyromonas gingivalis promotes colorectal cancer development by regulating NLRP3 inflammasome signaling
Authors: Zhi Wang, Xi Wang, Yiqun Jia
Journal: Cancer Research (2019)

Abstract Metagenomic analyses indicate that Porphyromonas spp. is associated with human colorectal carcinoma (CRC), however, whether this is an indirect or causal link remains unclear. We found that Porphyromonas gingivalis (P. gingivalis) were enriched in human stool or FFPE samples from colorectal carcinoma patients compared to colorectal adenoma or healthy subjects. Two colorectal cohort studies demonstrated that P. gingivalis infection was associated with poor prognosis of CRC. Moreover, in the ApcMin/+ mouse model of colorectal tumorigenesis, P. gingivalis increases tumor counts and in the orthotopic rectal MC38 carcinoma model increases tumor growth. Furthermore, tumors from orthotopic MC38 model exposed to P. gingivalis exhibited a tumor-infiltrating myeloid cells recruiting signature that was confirmed in human P.gingivalis-positive colorectal carcinomas. We next evaluated the role of NLRP3 in P. gingivalis promoting on CRC progression. When comparing with wild type mice, the increased tumor growth was subtracted in Nlrp3-/- mice by the same orthotopic MC38 model exposed to P. gingivalis. To determine relevant cell compartment responsible for NLRP3 function, we generated Nlrp3-/- chimeric mice with adoptive bone marrow transplantation by using the same orthotopic tumor model. The results showed the effect of NLRP3 on P. gingivalis pathogenesis was from both hematopoietic and non-hematopoietic sources. Additionally, we performed expression profile to show that NLRP3 attenuates multiple pathways associated with P. gingivalis promoting colorectal cancer development. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells by regulating NLRP3 inflammasome activity, P. gingivalis generates a proinflammatory microenvironment that is conductive for colorectal neoplasia progression. Note: This abstract was not presented at the meeting. Citation Format: Zhi Wang, Xi Wang, Yiqun Jia. Porphyromonas gingivalis promotes colorectal cancer development by regulating NLRP3 inflammasome signaling [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 2358.
Abstract 698: Enhancing apoptosis to improve the therapy of <i>EGFR</i>-mutant lung cancer
Authors: Kosuke Tanaka, Song Han, Yogesh T. Ganesan, James J. Hsieh, Emily H. Cheng
Journal: Cancer Research (2019)

Abstract EGFR-TKIs have shown clinical efficacy in EGFR-mutant lung cancer patients, but most of the cases eventually develop resistance to the drugs, including the third-generation EGFR-TKI. Here, we develop a cell death mechanism-based combination strategy to enhance the therapeutic effect of EGFR-TKIs as well as to overcome the acquired resistance to EGFT-TKI in EGFR-mutant lung cancer. Through high-throughput screening of a custom pathway inhibitor library (-1000 drugs), we discovered Aurora kinase inhibitors that synergized with a third-generation EGFR-TKI (AZD9291) to induce apoptosis in EGFR-mutant lung cancer cells. Aurora kinase inhibitors enhanced AZD9291-mediated induction of BIM and PUMA, two important sentinels interconnecting the EGFR signal transduction pathway and the mitochondrial apoptotic machinery BAX and BAK. Combined inhibition of Aurora kinases and EGFR prevented the emergence of EGFR-TKI resistant clones in clonogenic assays. Interestingly, AZD9291 resistant lung cancer cells exhibited greater sensitivity to Aurora kinase inhibitors compared with parental cells. In conclusion, we found that the combination of AZD9291 and Aurora kinase inhibitors synergistically induced BIM and PUMA-mediated apoptosis, which may render a promising strategy to improve the therapy of EGFR-mutant lung cancer. &amp;lt;!–EndFragment–&amp;gt; Citation Format: Kosuke Tanaka, Song Han, Yogesh T. Ganesan, James J. Hsieh, Emily H. Cheng. Enhancing apoptosis to improve the therapy of EGFR-mutant lung 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 698.
Abstract 4637: Non-stem cell-driven colonic tumors retain an intestinal differentiation hierarchy
Authors: Cherie R. Scurrah, Alan J. Simmons, Eunyoung Choi, Robert J. Coffey, James R. Goldenring, Ken S. Lau
Journal: Cancer Research (2019)

Abstract Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States. Cancer stem cells (CSCs) play critical roles in therapeutic resistance, tumor recurrence, and metastasis that lead to patient death. We propose to evaluate the properties of CSCs in the context of the tumor cell-of-origin, the cell that initiates oncogenesis. We hypothesize that the tumor cell-of-origin is directly related to the CSCs present in tumors that consequently arise. To test this hypothesis, the stem-like properties of CSCs from stem cell- and non-stem cell-driven tumors, initiated from the Lrig1 and Mist1 promoters, respectively, were analyzed and compared through the use of lineage mapping and single-cell RNA-sequencing. We observed that although Mist1-expressing non-stem cells do not exhibit stem cell behavior under homeostatic or damage conditions, they can serve as tumor cells-of-origin. These tumors maintain a differentiation hierarchy that is lacking in stem cell-driven tumors. These results suggest that the origin of tumorigenesis influences tumor CSCs and thus tumor characteristics which could be utilized for the development of novel therapies. Citation Format: Cherie R. Scurrah, Alan J. Simmons, Eunyoung Choi, Robert J. Coffey, James R. Goldenring, Ken S. Lau. Non-stem cell-driven colonic tumors retain an intestinal differentiation hierarchy [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 4637.
Abstract 3697: Optimization of human cancer cell xenografts into zebrafish larvae for high-throughput drug screening
Authors: Stephen R. Dockins, Jessica S. Blackburn, Meghan G. Haney, Bradley Wilson
Journal: Cancer Research (2019)

Abstract The use of zebrafish in cancer xenograft models has grown rapidly in recent years. This is primarily due to the fact that this model takes advantage of the ease of in vivo imaging and the high-throughput screening capabilities that zebrafish have to offer. However, researchers have yet to come to a consensus on standardized procedure to utilize zebrafish for xenograft of human cells. This study aims to optimize a zebrafish xenografting protocol for various human cancers with the intention of performing high-throughput drug screening. We tested the survival of 3 different zebrafish strains when incubated at 28°C, 34°C and 37°C. There was no difference in survival between the AB, SAT, and Casper strains of zebrafish at any temperature. Human leukemia, breast, lung, colon, and brain cancer cell lines were fluorescently labelled with Vybrant DiI cell staining dye and injected at a concentration of 100, 250, 500, or 1000 cells per 2nL droplet volume into dechorionated 2-day-old zebrafish embryos. The injection sites used were the brain, caudal vein, duct of Cuvier (DC), eye, pericardium, perivitelline space (PVS), and yolk sac. As expected, injections became more difficult and time consuming when using higher cell counts as the injector needle clogged more often. Similarly, injection sites that required more precision like the caudal vein or eye took the longest to inject successfully and had lower engraftment rates than sites like the yolk or DC. We determined that using 500 cells per injection was optimal as engraftment level was comparable to 1,000 cell injections but had improved survival and reduced injection time. Optimal injection site varied between cell lines, but overall, injections into the duct of Cuvier resulted in consistently high survival and engraftment rates with one of the lowest injection times. We are in the process of determining the extent to which the injection site affects chemotherapy response on human cells implanted into zebrafish. We are also preforming a high-throughput drug screen on human leukemia cells implanted into zebrafish to provide proof-of-principle that these methods are useful in identifying novel anti-cancer compounds. In total, this work will establish standard operating procedures for use of xenograft in zebrafish, providing new opportunities in personalized medicine and drug discovery. Citation Format: Stephen R. Dockins, Jessica S. Blackburn, Meghan G. Haney, Bradley Wilson. Optimization of human cancer cell xenografts into zebrafish larvae for high-throughput drug screening [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 3697.
Abstract 3336: Changes in prescriptions for breast cancer medications after Medicaid expansion
Authors: Johanna Catherine Maclean, Michael T. Halpern, Steven C. Hill, Michael F. Pesko
Journal: Cancer Research (2019)

Abstract Introduction: As of summer 2018, 34 states have expanded Medicaid eligibility under the Affordable Care Act. While the Medicaid expansions decreased rates of being uninsured among women with breast cancer and increased early breast cancer detection, it is unknown whether expansions increased receipt of medications used to prevent and treat breast cancer. This study examines differences over time in receipt of two types of breast cancer hormonal therapies (tamoxifen and aromatase inhibitors) and associated payments for these medications in states that did vs. did not expand Medicaid during the period 2011-2017. Methods: The study’s data source is the Medicaid State Drug Utilization Database (SDUD). This data set, compiled by the Centers for Medicaid and Medicare (CMS), is administrative data submitted by state Medicaid programs. The data comprise outpatient prescription medications that are covered under the Medicaid Drug Rebate Program for which Medicaid serves as a third-party payer; this includes aggregate numbers of prescriptions and associated payments for individuals enrolled in both fee for service and managed care Medicaid programs. Both branded and generic prescriptions for three aromatase inhibitors (anastrozole, exemestane, and letrozole) were included in the study’s analyses. Analyses used differences-in-differences and event study models (controlling for state characteristics) to compare changes in Medicaid expansion states to changes in non-expansion states before vs. after expansion. Results: Initial regression analyses indicate that prescriptions for all hormonal therapy medications increased by 27% (p&amp;lt;0.05) and prescriptions for aromatase inhibitors (branded and generics combined) increased by 29% (p&amp;lt;0.05) in expansion states relative to non-expansion states. Prescriptions for tamoxifen and for generic aromatase inhibitors only also increased significantly. Post-expansion, both total payments and Medicaid payments for all hormonal therapies increased by 13% (p&amp;lt;0.01) in expansion states relative to non-expansion states. The similar increases for total and Medicaid payments suggest that state Medicaid programs, not patients, financed the increased hormonal therapy prescription payments. Conclusions: Our findings indicate that states that expanded Medicaid with the ACA experienced increased prescriptions for breast cancer hormonal therapies relative to states that did not expand Medicaid; this effect of Medicaid expansion increased over time. The increased prescriptions were financed by Medicaid, not by patients. Citation Format: Johanna Catherine Maclean, Michael T. Halpern, Steven C. Hill, Michael F. Pesko. Changes in prescriptions for breast cancer medications after Medicaid expansion [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 3336.
Abstract 181: Prolyl-4-hydroxylase α subunit 3 promotes renal cancer progression and metastasis
Authors: Larry E. Broome, Bingzhi Wang, Menghuang Zhao, Junhua Yang, Hakim Bouamar, Matyas Cserhati, Lu-Zhe Sun
Journal: Cancer Research (2019)

Abstract Collagen is the major component of the extracellular matrix, its overexpression has been shown to facilitate tumor development and progression. Prolyl-4-hydroxylase α subunit 3 (P4HA3) plays a crucial role in the synthesis of collagen, as it is involved in the catalysis to convert proline residues to 4 hydroxyproline residues, which are essential for the conformational stability of mature collagen. It has been reported that P4HA3 functions as a tumor promoter in gastric cancer. However, the role of P4HA3 in renal cell carcinoma (RCC) has not been established. To identify the role of P4HA3 in RCC, we analyzed the expression of P4HA3 in RCC patients and knocked down the expression of P4HA3 in two renal cancer cell lines with different P4HA3 siRNAs and P4HA3 shRNAs. We performed cell proliferation, migration and invasion assays in vitro and in vivo. Our results demonstrated that expression of P4HA3 was upregulated in RCC patients and knockdown of P4HA3 significantly inhibited renal cancer cell proliferation, migration and invasion. Mouse xenograft studies demonstrated the tumor promoting role of P4HA3 in renal cancer. Therefore, P4HA3 appears to be a potential therapeutic target for the treatment of RCC. Citation Format: Larry E. Broome, Bingzhi Wang, Menghuang Zhao, Junhua Yang, Hakim Bouamar, Matyas Cserhati, Lu-Zhe Sun. Prolyl-4-hydroxylase α subunit 3 promotes renal cancer progression and 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 181.
Abstract 2397: Pre-clinical evaluation of PE0116: A potent cross-linking depednet 4-1BB agonist antibody
Authors: Ningning Song, Zhengwu Li, Shan He, Teddy Yang, Qing Duan
Journal: Cancer Research (2019)

Abstract 4-1BB is a member of the tumor necrosis factor superfamily and plays a critical role in activation of cytotoxic T cells to promote anti-tumor immunity. As a co-stimulatory molecule, it is ideally suited for activation via agonist therapeutic antibodies in order to reactivate the immune system and promote cytolytic activity through CD8+ T cells. Clinical trials of two agonist antibodies (Urelumab and Utomilumab) are ongoing. Urelumab has shown clinical efficacy but been hampered by inflammatory liver toxicity at doses above 1 mg/kg, suggesting potential safety concerns at higher doses. Utomilumab has a superior safety profile, but is a less potent 4-1BB agonist. Hence, it may be necessary to achieve potent immune activation while avoiding limiting immune-related adverse events. PE0116 is a fully human monoclonal antibody generated from immunization of Harbour H2L2 human transgenic mice with recombinant human 4-1BB protein. It blocks the binding of 4-1BB to its ligand 4-1BBL and its activity in T cell activation is crosslinking dependent. After crosslinking, PE0116 strongly increases IFNg secretion from T cells in the presence of anti-CD3 antibody and its activity is superior to Utomilumab analog. More importantly, PE0116 has demonstrated robust anti-tumor activity and better potency than both benchmark antibodies in MC38 tumor model with human 4-1BB KI mice. PE0116 has also demonstrated good safety profile in a non-GLP safety study in cyno monkey. Currently the antibody is under late stage IND-enabling study. Its safety and efficacy will be further tested in patients. Citation Format: Ningning Song, Zhengwu Li, Shan He, Teddy Yang, Qing Duan. Pre-clinical evaluation of PE0116: A potent cross-linking depednet 4-1BB agonist antibody [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 2397.
Alcohol complicates multimorbidity in older adults
Authors: Duncan Stewart, Jim McCambridge
Journal: BMJ (2019)

Lower birth rates and higher life expectancy are transforming global population age profiles, such that the prevalence of long term health conditions in the general population is rising steeply, with more people living with multimorbidity as they age. 1 Most people aged 65 or over have multiple conditions, 1 and the proportion with multimorbidity can be expected to increase further.Trends in alcohol consumption show higher levels of unhealthy drinking among older birth cohorts in high income countries, and older people in the UK drink more than those in other European countries, Australasia, and North America. 2 The challenges of clinical management of older adults with multimorbidity are made more difficult by alcohol consumption, even at low doses.
Abstract 12385: The Impact of Body Mass Index on Early Mortality and Morbidity After Coronary Artery Bypass Grafting in Elderly Patients: Emaciation versus Obesity —Which is Worse? —
Authors: Naritomo Nishioka, Hiroaki Miyata, Ko Bando, Noboru Motomura, Nobuya Koyama, Shun Kohsaka, Shin-ichi Takamoto, Kazuhiro Hashimoto
Journal: Circulation (2017)

Objective: The objective of this study was to investigate the relationship between body mass index and early mortality and morbidity for elderly patients who underwent coronary artery bypass grafti...
Phase 1 study of CA-4948, a novel inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) in patients (pts) with r/r non-Hodgkin lymphoma.
Authors: Allison Claire Rosenthal, Han W. Tun, Anas Younes, Grzegorz S. Nowakowski, Matthew Alexander Lunning, Krish Patel, Daniel Jeffrey Landsburg, Robert E. Martell, Lori Ann Leslie
Journal: Journal of Clinical Oncology (2019)

e19055 Background: IRAK4 is a signaling modulator of Toll-like receptors (TLRs) and members of the IL-1R family. TLR/IL-1R activity is frequently dysregulated in NHL, including DLBCL and Waldenström macroglobulinemia (WM). CA-4948, an oral inhibitor of IRAK4, has demonstrated anti-tumor activity in preclinical models. Methods: Dose finding cohorts (3+3 design) will test QD or BID dosing schedule in pts with R/R NHL. Dose expansion will occur in 2 cohorts of R/R NHL with or without MYD88 mutation at the RP2D or MTD. Key eligibility criteria: age ≥ 18 years, ECOG ≤1, and adequate organ function. Objectives: safety, MTD and RP2D (primary); PK and anti-tumor activity (secondary); exploratory biomarkers and PD effects. Plasma cytokine levels are being evaluated post ex-vivo TLR stimulation in whole blood. Results: 13 pts have been treated (6 at 50 mg QD; 3 at 100 mg QD; 4 at 50 mg BID). Tumor types included DLBCL (7), FL (5), WM (1). The most frequent treatment-emergent AEs (≥10% of pts) were fatigue (23%), conjunctivitis, constipation, neutrophil count decrease, white blood cell count decrease (each 15%). One pt treated at 100 mg QD experienced Gr 3 rash which resolved following oral steroid treatment; dose reduction to 50 mg QD was tolerated without flare up. One SAE of disease progression occurred. 9 pts completed the DLT evaluation period thru Cycle 2 including 2 ongoing in Cycle 4 and 6. Preliminary PK showed that CA-4948 is rapidly absorbed with maximum plasma concentration observed 1.0 to 4.0 hrs post administration. T 1/2 in plasma was about 6 hrs. Minimal to no accumulation was observed following multiple doses. Plasma exposures were dose proportional. Preliminary PD data showed, similar to murine studies, on target reduction of NF-kB-associated factors such as IL-6 post-treatment from pts with complete sample sets (N = 8). Conclusions: Current dose/schedule is well tolerated with preliminary PK and PD effects at the initial dose level. MTD has not been reached. Clinical trial information: NCT03328078.
Abstract 4412: Piperine enhances the efficacy of 5 FU against liver cancer
Authors: David Anwanwan, Santosh Kumar Singh, James W. Lillard, Manoj K. Mishra, Rajesh Singh
Journal: Cancer Research (2019)

Abstract Liver cancer is one of the most devastating malignancies. Hepatocellular carcinoma (HCC) accounts for &amp;gt;90% of primary liver malignancies and is the third-leading cause of cancer-related deaths worldwide. Systemic chemotherapy is one of the most important treatment modalities for advanced HCC. Unfortunately, long-term treatment acquired resistance in HCC due to the activation of drug efflux pumps. A natural compound in combination with chemotherapeutic drugs is a potential approach to combat the side effects. In this study, we have demonstrated whether piperine (natural compound) could increase the effect of 5-FU in HCC cells. The cell viability (MTT) assay was performed to determine the optimal IC50 values of Piperine, 5-FU alone and in combination. Immunofluorescence study confirmed the effectiveness of combined drug; dead nuclei were found more within the cells treated by the combination compared to piperine or 5-FU alone. The combined drug treatment was most effective in inhibiting proliferation and inducing apoptosis; accordingly, it showed noticeable increases in pro-apoptotic (BAK, BID), PARP and decreases in anti-apoptotic genes (BCL-XL) gene in a western blot and RT-PCR analysis. Further, in SK-HEP-1 cells, the combination upregulated the expression of cell cycle inhibitors (p21WAF1/CIP1, p27KIP), which, in turn, inhibited the expression of CDK2/ Cyclin D1 complex. Therefore, it blocks the transition of cells into G0/G1 to S phase. Taken together, we observed that the combination of 5-FU and Piperine resulted in a significant cytotoxicity and apoptosis as compared to alone. Our results suggest that piperine can be a potential agent in enhancing the efficacy of 5-FU in liver cancer treatment. These finding highlights the promising role of natural bioactive compounds and provides the rationale for further transitional researches. Citation Format: David Anwanwan, Santosh Kumar Singh, James W. Lillard, Manoj K. Mishra, Rajesh Singh. Piperine enhances the efficacy of 5 FU against liver 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 4412.
Crisaborole 2% ointment for the treatment of intertriginous, anogenital, and facial psoriasis: A double-blind, randomized, vehicle-controlled trial
Authors: Peter W. Hashim, Margot Chima, Hee J. Kim, Jennifer Bares, Christopher J. Yao, Giselle Singer, Tinley Chen, Jordan Genece, Danielle Baum, Grace W. Kimmel, John K. Nia, Matthew Gagliotti, Mark G. Lebwohl
Journal: Journal of the American Academy of Dermatology (2019)
Immune signatures identify three immune clusters in mCRC, with potential clinical implications
Authors: L. Pedrosa, R. Moreno, F. Esposito, P. Jares, M. Cuatrecasas, E. Pineda, M. Español, L. Paré, N. De la Iglesia, D. Benitez, J. Camps, S. Church, M. Cascante, T. Thomson, A. Prat, J. Maurel
Journal: Annals of Oncology (2019)