tbuckley/cabot-search huggingface dataset:
Abstract 897: Lipid metabolism is involved in mitotic slippage-induced SASP upon treatment with anti-mitotic drugs
Authors: Karen C. Crasta, Alex Wong, Bryan Lim
Journal: Cancer Research (2019)

Abstract Aberrant lipid accumulation is a hallmark of cancer. However, there is little known regarding mechanisms linking lipid metabolism to chemotherapy-induced cell fates. Here, we describe lipid accumulation in cells following antimitotic drug-treatment. Cells arrested in mitosis, as well as cells that escaped mitotic arrest and underwent mitotic slippage, showed elevated cytoplasmic lipid droplets. Interestingly, we found that TOFA, an inhibitor that targets acetyl-CoA carboxylase (ACC) and blocks lipid accumulation enhanced survival of antimitotic-treated cells. Our work previously revealed that cells that survive slippage become senescent and confer pro-tumourigenic effects through non-cell-autonomous effects. Modulating lipid biosynthesis in cells post-slippage by TOFA amplified their inflammatory secretion profiles and accelerated development of tumourigenic behavior. In contrast to TOFA, inhibition of lipid accumulation by C75, a drug targeting fatty acid synthase, significantly reduced the production of pro-tumourigenic factors. This suggests that discrete lipid biosynthesis pathways could contribute differentially to the regulation of pro-tumourigenic inflammation. Note: This abstract was not presented at the meeting. Citation Format: Karen C. Crasta, Alex Wong, Bryan Lim. Lipid metabolism is involved in mitotic slippage-induced SASP upon treatment with anti-mitotic drugs [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 897.
Abstract 18979: Identification of a Novel Small Molecule That Regulates Lipid Metabolism by Enhancing ABCA1 Expression
Authors: Xiao Wang, Yongzhen Li, Chao Liu, Ni Li, Jinque Luo, Xuan Zuo, Yanni Xu, Shuyi Si
Journal: Circulation (2017)

Introduction and objectives: A large number of epidemiological studies have found that serum High-density lipoprotein cholesterol (HDL-C) level is inversely associated with the risk of atherosclero...
Realizing a Closed-Loop (Artificial Pancreas) System for the Treatment of Type 1 Diabetes
Authors: Rayhan A Lal, Laya Ekhlaspour, Korey Hood, Bruce Buckingham
Journal: Endocrine Reviews (2019)

Abstract Recent, rapid changes in the treatment of type 1 diabetes have allowed for commercialization of an “artificial pancreas” that is better described as a closed-loop controller of insulin delivery. This review presents the current state of closed-loop control systems and expected future developments with a discussion of the human factor issues in allowing automation of glucose control. The goal of these systems is to minimize or prevent both short-term and long-term complications from diabetes and to decrease the daily burden of managing diabetes. The closed-loop systems are generally very effective and safe at night, have allowed for improved sleep, and have decreased the burden of diabetes management overnight. However, there are still significant barriers to achieving excellent daytime glucose control while simultaneously decreasing the burden of daytime diabetes management. These systems use a subcutaneous continuous glucose sensor, an algorithm that accounts for the current glucose and rate of change of the glucose, and the amount of insulin that has already been delivered to safely deliver insulin to control hyperglycemia, while minimizing the risk of hypoglycemia. The future challenge will be to allow for full closed-loop control with minimal burden on the patient during the day, alleviating meal announcements, carbohydrate counting, alerts, and maintenance. The human factors involved with interfacing with a closed-loop system and allowing the system to take control of diabetes management are significant. It is important to find a balance between enthusiasm and realistic expectations and experiences with the closed-loop system.
BEACON CRC: a randomized, 3-Arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E–mutant metastatic colorectal cancer
Authors: S. Kopetz, A. Grothey, E. Van Cutsem, R. Yaeger, H. Wasan, T. Yoshino, J. Desai, F. Ciardiello, A. Gollerkeri, K. Maharry, F. Loupakis, Y. Hong, N. Steeghs, T. Guren, H. Arkenau, P. García Alfonso, V. Sandor, J. Christy-Bittel, L. Anderson, J. Tabernero
Journal: Annals of Oncology (2019)
Abstract 5231: Regulatory mechanism of carboxylesterase 2 expression and its role in human colorectal cancer
Authors: Momoko Ishimine, Hyeon-Cheol Lee, Hirofumi Nakaoka, Hajime Orita, Toshiyuki Kobayashi, Ituro Inoue, Koichi Sato, Takehiko Yokomizo
Journal: Cancer Research (2019)

Abstract Irinotecan (camptothecin-11 (CPT-11)) is an anticancer drug that has been used in the treatment of a wide spectrum of cancer, and irinotecan-containing regimens such as FOLFIRI and FOLFOXIRI are standard chemotherapy regimens for advanced colorectal cancer. Irinotecan is a prodrug that is converted to its active metabolite 7-ethyl-10-hydroxycamptothesin (SN-38) by carboxylesterases CES1 and CES2. CES2 has a far higher hydrolytic efficiency against irinotecan than CES1. Since CES2 expression is higher than other CES isozymes in colon tissue, it might contribute to local (i.e., intratumoral) activation of irinotecan. Recent studies have shown that CES2 expression is regulated by p53 in human colon carcinoma cell lines. TP53 is a tumor suppressor gene and the frequency of its mutations in colorectal cancer is approximately 50%. Therefore, TP53 mutation may cause downregulation of CES2 expression and affect the sensitivity of colorectal cancer to irinotecan. In our previous study, we showed that both CES2 expression and carboxylesterase activity were significantly lower in most colorectal cancer specimens than in adjacent normal tissue. Nevertheless, there was no clear relationship between CES2 expression and TP53 gene status. We also found that p21 expression was significantly reduced in the tumors compared with adjacent normal tissue independently of their TP53 mutational status. Notably, there was a strong positive correlation between p21 and CES2 expression even in the tumors with nonfunctional p53. Recent studies have reported that colorectal tumors developed in proximal colon (right side) and distal colon (left side) exhibit different molecular characteristics and histology. Patients with left-sided colorectal tumors respond well to conventional adjuvant chemotherapies, and the prognosis of these patients is better than that of patients with right-sided colorectal tumors. To test whether location of tumor affects CES2 expression, we compared the CES2 expression levels of tumors that arose from proximal colon with those from distal colon. We also tested the potency and the selectivity of a recently reported CES2 inhibitor. Our results provide important insights into the regulatory mechanism of CES2 expression and its role in colorectal cancer. Citation Format: Momoko Ishimine, Hyeon-Cheol Lee, Hirofumi Nakaoka, Hajime Orita, Toshiyuki Kobayashi, Ituro Inoue, Koichi Sato, Takehiko Yokomizo. Regulatory mechanism of carboxylesterase 2 expression and its role in human colorectal 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 5231.
Abstract 4703: Single Cell CNV End to End workflow to uncover tumor heterogeneity in a murine breast cancer model
Authors: Lee D. Gibbs, Jing Qian, Michelle Webb, Sharon Chang, Zarko Manojlovic, Enrique I. Velazquez, Troy McEachron, David W. Craig, John D. Carpten
Journal: Cancer Research (2019)

Abstract Background: Tumor heterogeneity is a hallmark of cancer and can have significant impact on identifying drivers, including those that may be therapeutically relevant. Although, the traditional sequencing of bulk tumor specimens provides invaluable information, sequencing of individual cells provides a true representation of the cellular heterogeneity that exists within a cancer. Novel technologies such as single cell copy number variation (scCNV) enable copy number profiling at a single cell resolution. Single Cell CNV generates genome wide sequencing libraries from single cells to reveal tumor heterogeneity and evolution of subclonal populations. Methods: In this study, we utilized a scCNV assay to assess heterogeneity within the 4T1 murine breast tumor model. To accomplish this we have developed an end-to-end workflow including tissue dissociation, single cell library preparation, sequencing and data analysis. We injected 4T1 cells into the mammary fat pad of 4-6 week old BALB/c mice. Mice were sacrificed at 21 days and tumors were removed from the injection site and dissociated using Milteny’s Biotec Octo Dissociator. We utilized the 10X Genomics Chromium system to partition single cells and prepare sequencing libraries in parallel such that all DNA fragments produced within a partition are barcoded. Following library construction, the Illumina Novaseq 6000 system was used to sequence single cell libraries. Additionally, single cell libraries from a fraction of the 4T1 cells that were injected into the mammary fat and non-metastatic isogeneic cell line variants, 67NR and 168FARN, were also sequenced. Results: We observed a pair of amplifications (&amp;gt;8 copies) on chromosome 9 and three segments of amplification on chromosome 15 that were conserved throughout the injection site tumor cells. Interestingly, the amplifications on chromosome 15 encompass one of the most commonly observed breast cancer oncogenes, Myc, and the cell migration regulator, Skp2. Further, we observed three unique cluster of tumors cells which suggests the possibility of detecting major and minor clonal populations using this technology. Conclusion: Our findings suggest scCNV will help us to improve characterizations of the entirety of a patient’s disease to uncover potential clones that are primed to induce metastasis, drug resistance, and relapse. Citation Format: Lee D. Gibbs, Jing Qian, Michelle Webb, Sharon Chang, Zarko Manojlovic, Enrique I. Velazquez, Troy McEachron, David W. Craig, John D. Carpten. Single Cell CNV End to End workflow to uncover tumor heterogeneity in a murine breast cancer model [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 4703.
Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy
Authors: Noor Momin, Naveen K. Mehta, Nitasha R. Bennett, Leyuan Ma, Joseph R. Palmeri, Magnolia M. Chinn, Emi A. Lutz, Byong Kang, Darrell J. Irvine, Stefani Spranger, K. Dane Wittrup
Journal: Science Translational Medicine (2019)

The clinical application of cytokine therapies for cancer treatment remains limited due to severe adverse reactions and insufficient therapeutic effects. Although cytokine localization by intratumoral administration could address both issues, the rapid escape of soluble cytokines from the tumor invariably subverts this effort. We find that intratumoral administration of a cytokine fused to the collagen-binding protein lumican prolongs local retention and markedly reduces systemic exposure. Combining local administration of lumican-cytokine fusions with systemic immunotherapies (tumor-targeting antibody, checkpoint blockade, cancer vaccine, or T cell therapy) improves efficacy without exacerbating toxicity in syngeneic tumor models and the BrafV600E /Ptenfl/fl genetically engineered melanoma model. Curative abscopal effects on noncytokine-injected tumors were also observed as a result of a protective and systemic CD8+ T cell response primed by local therapy. Cytokine collagen-anchoring constitutes a facile, tumor-agnostic strategy to safely potentiate otherwise marginally effective systemic immunotherapies.
Burnout and Career Satisfaction Among U.S. Cardiologists
Authors: Laxmi S. Mehta, Sandra J. Lewis, Claire S. Duvernoy, Anne K. Rzeszut, Mary Norine Walsh, Robert A. Harrington, Athena Poppas, Mark Linzer, Philip F. Binkley, Pamela S. Douglas
Journal: Journal of the American College of Cardiology (2019)
Abstract 2387: NKG2A-antagonizing monoclonal antibodies identified through phage display
Authors: Jing Gao, Lili Hu, Ruirui Sui, Cuicui Guo, Lina Wang, Teddy Yang, Jack Han, Qing Duan, Louis Liu
Journal: Cancer Research (2019)

Abstract The inhibitory receptor NKG2A-CD94 is mainly expressed on NK cells and some T cell and mediates an inhibitory signal through association with a non-classical MHC class I molecule HLA-E, which is commonly over-expressed in human cancers. Targeting NKG2A with monoclonal antibody holds potentials in immunotherapy of cancer. However, proteins with homologous sequences such as NKG2C/CD94 or NKG2E/CD94 complexes generally deliver an activating signal upon ligand binding. NKG2A-specific antagonizing antibodies would be needed to further explore therapeutic potentials of targeting NKG2A for immunotherapy of cancer. We have developed and characterized panels of monoclonal antibodies (mAbs) that specifically recognize NKG2A. Balb/c or SJL mice had been immunized with recombinant NKG2A/CD94 protein, recombinant plasmids encoding hNKG2A or stable cell line with ectopic expression of hNKG2A. Splenocytes from such immunized animals were collected for construction of phage-displayed antibody library in a single chain variable fragment (scFv) format. The NKG2A-specific antibodies, that had no binding to NKG2C, NKG2E or CD94, were isolated through multiple rounds of phage panning and ELISA-based screening. Such antibodies also block HLA-E ligand binding and enhanced cytotoxicity of NK cell lines and primary NK cells on cancer cells. In summary, isolation and characterization of a panel of NKG2A-specific antagonizing antibodies enable us to further determine the feasibility of NKG2A-targeted immunotherapy of cancer. Citation Format: Jing Gao, Lili Hu, Ruirui Sui, Cuicui Guo, Lina Wang, Teddy Yang, Jack Han, Qing Duan, Louis Liu. NKG2A-antagonizing monoclonal antibodies identified through phage display [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 2387.
Abstract 15456: Computer-assisted Diagnosis of Coronary Angiography
Authors: S.M.Reza Soroushmehr, Abhishek Bafna, Sinha Shashank, Nallamothu Brahmajee, Kevin Ward, Kayvan Najarian
Journal: Circulation (2015)

Introduction: Current analysis of coronary angiograms (CAs) relies on visual estimation by human operators with several limitations. Techniques like quantitative coronary angiography are available but require significant user input. A fully-automated system would be useful in guiding diagnosis and quality assurance of CAs. Methods: We obtained 56 CAs from a random cohort at the University of Michigan from 2010-2012. Studies were limited to nonobstructive coronary disease to facilitate early development of programming. Image processing techniques were employed in 20 test cases to fully-automate interpretation and was compared to visual estimation by a physician annotating images. Programming was done in MATLAB. Results: In 56 CAs with annotation, the algorithm was able to correctly identify 133/146 lesions, yielding an accuracy of 91%. The figure shows an example where a right coronary artery lesion was correctly identified. Major challenges were surmounted, including vessel identification, motion and extrinsic artifacts (e.g, catheters), morphological operations using a branch-point vessel skeleton, and vessel tracking and thickness estimation through edge detection. Conclusions: We demonstrate proof-of-concept for a fully-automated system for analyzing CAs that showed excellent correlation with annotated data. Future studies will need to develop the system for more complex cases and to explore its clinical and quality implications.
Abstract 2384: TAK-169, an exceptionally potent CD38 targeted engineered toxin body, as a novel direct cell kill approach for the treatment of multiple myeloma
Authors: Erin K. Willert, Garrett L. Robinson, Jack P. Higgins, Jensing Liu, Janice Lee, Sakeena Syed, Yuhong Zhang, Dan Tavares, Anya Lublinsky, Nibedita Chattopadhyay, Haiqing Wang, Laura Packer, Pu Shi, Carole Harbison, Sanjay Patel, John Newcomb
Journal: Cancer Research (2019)

Abstract Advances in the treatment of multiple myeloma have been driven by the development of new modalities, including proteasome inhibitors, immunomodulatory agents and monoclonal antibodies. TAK-169 is an engineered toxin body (ETB) comprising a proprietarily engineered, deimmunized form of the ribosome inactivating Shiga-like toxin A-subunit (SLTA) genetically fused to an antibody fragment that specifically targets the CD38 cell surface receptor. Although CD38 is a poorly internalizing receptor, TAK-169 is able to efficiently internalize and directly kill CD38-expressing cells through the enzymatic and irreversible inhibition of protein synthesis. This novel mechanism of action may be relevant in patients who have progressed after or are unlikely to respond to CD38-targeted antibody therapy. A library of unique CD38-targeting antibodies fused to deimmunized SLTA was screened in a variety of efficacy and safety models to identify TAK-169. TAK-169 demonstrated potent cytotoxicity across a range of myeloma cell lines with a range of CD38 expression in vitro as well as in patient-derived samples including with previous exposure to daratumumab. TAK-169 retains activity in whole blood and PBMCs, indicating that the presence of red blood cells is not restrictive to cytotoxicity. Furthermore, TAK-169 retains activity in the presence of excess approved, CD38 targeted therapeutic daratumumab. TAK-169 is efficacious in several myeloma xenograft models, both subcutaneous and disseminated. Complete regressions were observed using both a once-weekly and bi-weekly schedule. In addition, a syngeneic model cell line expressing human CD38 was shown to be responsive to TAK-169 treatment in an immunocompetent mouse model, suggesting the possibility of immune mediated cell death induced by TAK-169. Tolerability studies in non-human primates demonstrate that repeat administration is tolerated at doses expected to be efficacious. Takeda Pharmaceuticals and Molecular Templates jointly discovered TAK-169 and are co-developing the molecule for the treatment of multiple myeloma. TAK-169 is expected to enter clinical studies in 2019. Citation Format: Erin K. Willert, Garrett L. Robinson, Jack P. Higgins, Jensing Liu, Janice Lee, Sakeena Syed, Yuhong Zhang, Dan Tavares, Anya Lublinsky, Nibedita Chattopadhyay, Haiqing Wang, Laura Packer, Pu Shi, Carole Harbison, Sanjay Patel, John Newcomb. TAK-169, an exceptionally potent CD38 targeted engineered toxin body, as a novel direct cell kill approach for the treatment of multiple myeloma [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 2384.
Abstract 1954: Tracking of orally-administered particles within the gastrointestinal tract of murine models using multispectral optoacoustic tomography
Authors: Neal Bhutiani, Abhilash Samykutty, Kelly McMasters, Nejat Egilmez, Lacey R. McNally
Journal: Cancer Research (2019)

Abstract While particle carriers have potential to revolutionize disease treatment, using these carriers requires knowledge of spatial and temporal biodistribution. The goal of this study was to track orally administered particle uptake and trafficking through the murine gastrointestinal (GI) tract using multispectral optoacoustic tomography (MSOT). Polylactic acid (PLA) particles encapsulating AlexaFluor 680 (AF680) dye conjugated to bovine serum albumin (BSA) were orally gavaged into mice. Particle uptake and trafficking were observed using MSOT imaging with subsequent confirmation of particle uptake via fluorescent microscopy. Mice treated with PLA-AF680-BSA particles exhibited MSOT signal within the small bowel wall at 1 and 6 h, colon wall at 6, 12, and 24 h, and mesenteric lymph node 24 and 48h. Particle localization identified using MSOT correlated with fluorescence microscopy. Despite the potential of GI tract motion artifacts, MSOT allowed for teal-time tracking of particles within the GI tract in a non-invasive and real-time manner. Future use of MSOT in conjunction with particles containing both protein-conjugated fluorophores as well as therapeutic agents could allow for non-invasive, real time tracking of particle uptake and drug delivery. Citation Format: Neal Bhutiani, Abhilash Samykutty, Kelly McMasters, Nejat Egilmez, Lacey R. McNally. Tracking of orally-administered particles within the gastrointestinal tract of murine models using multispectral optoacoustic tomography [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 1954.
Abstract 2930: Baicalein attenuates radiation-induced enteritis by improving endothelial dysfunction
Authors: Hyosun Jang, Sunhoo Park, Sehwan Shim, Jae Kyung Myung
Journal: Cancer Research (2019)

Abstract Background: Radiation-induced intestinal injury is frequently observed following clinical application of radiation for abdominal and pelvic cancers or occurs secondary to radiation exposure following a nuclear accident. Radiation-induced enteritis may be considered an ideal model of gastrointestinal inflammation. The endothelium is a crucial component of inflammation, and the endothelial dysfunction following radiation exposure induces the intestinal proinflammatory response and progression of radiation enteritis. Baicalein (5,6,7-trihydroxyflavonoid) is a flavonoid from Scutellaria baicalensis used in oriental herbal medicine. Baicalein has been found to have multiple beneficial properties including antioxidant, anti-inflammatory, anti-allergic, and anti-cancer activities. Here, we investigated the therapeutic effects of baicalein on endothelial dysfunction in radiation-induced intestinal inflammation. Methods: We performed histological analysis, bacterial translocation assays, and intestinal permeability assays, and also assessed infiltration of leukocytes and inflammatory cytokine expression using a radiation-induced enteritis model. In addition, to investigate the effect of baicalein in endothelial dysfunction, we analyzed endothelial-derived adherent molecules in human umbilical vein endothelial cells and irradiated intestinal tissue. Results: Histological damage such as shortening of villi length and impaired intestinal crypt function was observed in the radiation-induced enteritis model. However, intestinal damage was attenuated in baicalein-treated groups with improvement of intestinal barrier function. Baicalein inhibited the expression of radiation-induced adherent molecules in the endothelial cells and increased leukocyte infiltration in the irradiated intestine. We also determined that baicalein could accelerate crypt regeneration via recovery of endothelial damage. Conclusions: Baicalein has a therapeutic effect on radiation-induced intestinal inflammation by attenuating endothelial damage. &amp;lt;!–EndFragment–&amp;gt; Citation Format: Hyosun Jang, Sunhoo Park, Sehwan Shim, Jae Kyung Myung. Baicalein attenuates radiation-induced enteritis by improving endothelial dysfunction [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 2930.