tbuckley/cabot-search huggingface dataset:
Abstract 5278: Separate and combined effects of metabolic reprogramming interventions, autophagy inhibition, and carboplatin on murine triple-negative breast cancer cells
Authors: Alyssa J. Cozzo, Michael F. Coleman, Ciara H. O'Flanagan, Jane B. Pearce, Magdalena A. Rainey, Stephen D. Hursting
Journal: Cancer Research (2019)

Abstract Triple-negative breast cancers (TNBC) are an aggressive BC subset currently lacking targeted therapies. TNBCs exhibit aberrant fuel metabolism, including increased flux through glycolysis and the pentose phosphate pathway, increased lactate production (Warburg metabolism), and elevated dependence on glutamine (glutaminolysis). While dietary interventions such as caloric restriction, intermittent fasting, or ketogenic diets have demonstrated benefits (e.g, reduced tumor incidence, progression, and sensitization to some chemotherapeutic agents) in preclinical BC models, translation to humans has proven challenging, and concerns remain regarding tolerance and long-term safety of extreme diets in cancer patients. We hypothesized that targeted disruption of select metabolic pathways could recapitulate the beneficial effects of the aforementioned dietary interventions and improve the efficacy of carboplatin, part of first-line chemotherapy for primary and metastatic TNBCs. Moreover, we posited that blocking autophagy would further enhance the anticancer effects of metabolic reprogramming interventions (MRIs) alone and in combination with carboplatin. To test these hypotheses, we are using a high-throughput screening approach employing several MRIs with or without the addition of chloroquine and/or carboplatin in vitro. Serum starvation (an in vitro model of caloric restriction), rapamycin, BMS-754807 (a dual IGF-1R/insulin receptor), and nicotinamide significantly reduced cell viability (assessed by MTT assay) and clonogenicity (assessed by colony formation assay) of M-Wnt and M6 cells, both well-characterized TNBC cell lines derived from mammary tumors of MMTV-Wnt-1 and C3-TAg transgenic mice, respectively. The growth suppressive effects of these MRIs were further enhanced when combined with autophagy inhibition via chloroquine (CQ). Treatment of M-Wnt and M6 cells with CQ (20-80 µM) also increased in vitro cytotoxicity of carboplatin. Ongoing analyses and planned in vivo studies will confirm whether co-treatment with MRIs and/or CQ are an effective strategy for increasing the efficacy of carboplatin in TNBC cells. Citation Format: Alyssa J. Cozzo, Michael F. Coleman, Ciara H. O'Flanagan, Jane B. Pearce, Magdalena A. Rainey, Stephen D. Hursting. Separate and combined effects of metabolic reprogramming interventions, autophagy inhibition, and carboplatin on murine triple-negative breast cancer cells [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 5278.
Abstract 2154: A novel dual-function polymeric scaffold for cancer drug screening
Authors: Tianfu Wu, Zuan-Tao Lin
Journal: Cancer Research (2019)

Abstract Cell-based assay has been used as a conventional strategy for discovery of new anti-cancer drugs in pharmaceutical industries. Traditionally, two-dimensional (2D) cell culture based cytotoxicity assays are the most common approaches, despite the fact that they have significant limitations in simulating tissue or organ microenvironment. In comparison, 3-dimensional (3D) cell culture provides a more promising tool for new drug discovery, however, next-generation cell growth monitoring device for 3D cell culture is still challenging. Recent studies have shown the potential of metallic nanoparticle-polymeric composites in biosensing systems. We hypothesize that in a polymer-based 3D-cell culture system, cancer cell growth and the subsequent spheroid formation can cause structural change of the polymer network. With the incorporation of metallic nanoparticles into the polymeric network, electrical conductance change of the 3D-scafold may be monitored to reflect cell growth and spheroid formation. Here, we developed a dual-function polymer scaffold (DPS) by integrating thermosensitive polymers, silver flake-decorated polymers, and gNP-decorated polymers as a biosensor to monitor cancer cell growth. We found that the Triple negative breast cancer stem cell line MDA-MB-231 formed spheroid in DPS. It is notable that the increase of cancer cell numbers during the formation of spheroid was proportional to the change of electrical conductance of the 3D-scafold. Importantly, the results from DPS cell growth monitoring method correlate well with conventional cell counting during 3D cell culture of breast cancer cells. SEM imaging and AFM imaging have confirmed the integration of silver flakes and gold nanoparticles in the DPS. Finally, we demonstrated that the DPS 3D-scafold exhibited robust responses to MDA-MB-436 cells when exposed to 3 nM of paclitaxel (PTX) and docetaxel (DTX), respectively. This dual-function 3D-scaffold, for both cell growth and growth monitoring may have a good potential in drug screening in the future. Note: This abstract was not presented at the meeting. Citation Format: Tianfu Wu, Zuan-Tao Lin. A novel dual-function polymeric scaffold for cancer 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 2154.
Abstract 16919: Third Grade Academic Performance and Episodes of Care Among Children With Congenital Heart Defects
Authors: Stephanie E Watkins, Alex R Kemper, Alfred D’Ottavio, Manuela Wiedemeier, Robert Meyer, Nathaniel Greene, Timothy M Hoffman, Charlie Sang, Joseph Paolillo, Michael J Walsh, Jennifer S Li
Journal: Circulation (2018)

Introduction: Children with Congenital Heart Defects (CHD) may be at risk for poor academic performance in elementary school. Cumulative episodes of care among children with CHD may impact neurocognitive outcomes. We examined the association between the number of episodes of care and third-grade academic performance among children with CHD. Methods: We identified children with CHD from electronic medical records between 1/1/2008 and 12/31/2013 among five North Carolina (NC) tertiary care centers. We classified children by CHD type (severe disease, shunt lesion, valve disease, other) and matched subjects to the NC Department of Public Instruction educational records. We calculated the number of episodes of care by adding inpatient and outpatient visits from the EMR in the follow up period prior to administering the EOG. We estimated the odds of failing third-grade reading or math end of grade (EOG) tests among children with CHD who had episodes of care &gt;50 th percentile compared to children ≤50 th percentile using logistic regression controlling for maternal education, race/ethnicity, and gestational age. We also estimated the average change in the developmental scale score using linear regression for the same comparison group. The inability to demonstrate proficiency in NC grade level standards was considered a failing score. Results: A total of 425 children with CHD had third-grade EOG scores. Of these, 57% were male and 45% of children had a severe CHD, 30% had a shunt lesion, and 21% had valve disease. The median number of episodes of care was 4 (range: 1-60). Children with number of visits above the 50 th percentile (&gt;4 visits) had 2.09 (95% CI: 1.04,4.21) greater odds of failing the math EOG compared to children at or below the 50 th percentile (1-4 visits). The third- grade math developmental scale score declined by 1.54 points (p&lt;0.008) for every 10 episodes of care. There was no statistically significant effect of episodes of care on third grade reading performance. Conclusions: Children with CHD in NC with number of episodes of care above the 50 th percentile, may be at risk for delays in third-grade academic performance. Additional services may be required to improve academic success in this population.
Abstract 1208: Comparative analysis between DNA vs RNA-based T cell repertoire profiling for cancer immunotherapy
Authors: Shanker Kalyana-Sundaram, Christopher Traini, Wendy Halsey, Heather Jackson, Sabyasachi Bhattacharya, Niranjan Yanamandra, Ganesh Sathe, George Livi
Journal: Cancer Research (2019)

Abstract The T cell receptor (TCR), a defining structure of T cells is responsible for the recognition of the antigen-major histocompatibility complex, leading to the initiation of an immune response. The extreme diversity of the TCR repertoire represents a major analytical challenge. Massively parallel high throughput sequencing is commonly deployed to characterize various key features of T cell receptors including their clonal expansion and repertoire diversity. Genomic DNA is the most widely employed starting material to characterize the TCR repertoire. DNA is highly stable and contains a fixed copy number per cell, which allows for better quantification of TCR clones. However, the inclusiveness is a major limitation of using genomic DNA along with the PCR amplification challenges and sequencing errors due to recombined gene segments within the context of ‘unused’ segments and introns. Here we deploy RNA-based TCR profiling as an alternate strategy to overcome the major limitations associated with the DNA-based approach. Employing RNA with a simplified PCR amplification strategy allows a more comprehensive identification of unique TCR variants with greater sensitivity. It also provides information about expression levels of TCR sequences, and more importantly, excludes the non-productive sequences that are functionally irrelevant. In addition, Unique Molecular Indexing (UMIs) enables the determination of the absolute count of RNA transcripts processed in a sample, allowing straightforward error corrections. Citation Format: Shanker Kalyana-Sundaram, Christopher Traini, Wendy Halsey, Heather Jackson, Sabyasachi Bhattacharya, Niranjan Yanamandra, Ganesh Sathe, George Livi. Comparative analysis between DNA vs RNA-based T cell repertoire profiling for cancer immunotherapy [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 1208.
Abstract 4776: Characterizing an oncolytic adenovirus modified with the CXCL12 ligand for breast cancer therapy
Authors: Samia M. O'Bryan, J. Michael Mathis
Journal: Cancer Research (2019)

Abstract Breast cancer is the most commonly diagnosed cancer in women, making up nearly 30% of all diagnosed cancer cases each year. While localized breast cancer is easily treated, advanced cases are difficult to treat resulting in poor five-year survival rates. Thus, new therapies capable of increasing treatment efficacy are needed. Oncolytic virotherapy using human adenovirus is a novel therapeutic approach capable of specifically targeting cancer cells while sparing normal tissue. The adenovirus vector is well-characterized and is uniquely suited for oncolytic virotherapy due to its systemic stability, good safety profile and the ability to infect a broad range of dividing and non-dividing cells. Replication of oncolytic adenoviruses within cancer cells causes the lysis of the cells and subsequent spread of progeny virions within the surrounding tumor stroma. One challenge in targeting cancer cells with adenovirus vectors has been the low expression of the endogenous receptor, the Coxsackie and adenovirus receptor (CXADR), prompting the search for new receptor targets. In this study, we engineered an adenovirus to contain the CXCL12 ligand to target the chemokine receptors CXCR4 and CXCR7 overexpressed in a variety of tumors. Altered expression of these receptors drives tumor progression, migration, invasion and metastasis. Previously, we developed a bispecific adaptor molecule containing the CXCL12 ligand to redirect a replication-deficient wild-type adenovirus to breast cancer cells overexpressing CXCR4. In the current study, we engineered a replication-competent oncolytic adenovirus modified with the CXCL12 ligand to target cancer cells overexpressing CXCR4 and CXCR7. A recombinant gene was constructed using the tail domain of the adenovirus fiber gene fused to the trimerization domain of the T4 fibritin gene followed by the mature CXCL12 sequence. After viral production, the presence of a modified fiber and the CXCL12 ligand were confirmed. Subsequently, the vector was tested in a panel of breast cancer cells for infection and cell killing efficacy in vitro. Receptor knock down and overexpression studies confirmed the specificity of the virus. Together, these studies address the hypothesis that constructing a retargeted oncolytic adenovirus using the CXCL12 ligand provides selective infection and killing of breast cancer cells overexpressing CXCR4 and CXCR7. These results support the rationale for further development of retargeted adenovirus vectors for oncolytic virotherapy in patients. Future experiments will be conducted to assess tumor targeting using a xenograft mouse model of human breast cancer. Citation Format: Samia M. O'Bryan, J. Michael Mathis. Characterizing an oncolytic adenovirus modified with the CXCL12 ligand for breast cancer 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 4776.
Abstract LB-189: Pharmacological reactivation of MYC-dependent apoptosis cooperates with anti-PD1 immunotherapy
Authors: Heidi M. Haikala, Johanna M. Anttila, Mariel Savelius, Elsa Marques, Tiina Raatikainen, Mette Ilander, Henna Hakanen, Johanna Mattson, Paivi Heikkila, Marjut Leidenius, Heikki Joensuu, Satu Mustjoki, Panu Kovanen, Martin Eilers, Joel D. Leverson, Juha T. Klefström
Journal: Cancer Research (2019)

Abstract Elevated MYC levels sensitize tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK dramatically synergizes with BCL-2/BCL-XL inhibitors to activate MYC-dependent apoptosis. We demonstrate the translational potential of an AMPK and BCL- 2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with either navitoclax or venetoclax efficiently inhibits tumor growth, confers survival benefits and induces tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re- growth with presentation of PD1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by tumor resection and adjuvant metformin+venetoclax+anti-PD1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance. Citation Format: Heidi M. Haikala, Johanna M. Anttila, Mariel Savelius, Elsa Marques, Tiina Raatikainen, Mette Ilander, Henna Hakanen, Johanna Mattson, Paivi Heikkila, Marjut Leidenius, Heikki Joensuu, Satu Mustjoki, Panu Kovanen, Martin Eilers, Joel D. Leverson, Juha T. Klefström. Pharmacological reactivation of MYC-dependent apoptosis cooperates with anti-PD1 immunotherapy [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-189.
CDetection: CRISPR-Cas12b-based DNA detection with sub-attomolar sensitivity and single-base specificity
Authors: Fei Teng, Lu Guo, Tongtong Cui, Xin-Ge Wang, Kai Xu, Qingqin Gao, Qi Zhou, Wei Li
Journal: Genome biology (2019)

CRISPR-based nucleic acid detection methods are reported to facilitate rapid and sensitive DNA detection. However, precise DNA detection at the single-base resolution and its wide applications including high-fidelity SNP genotyping remain to be explored. Here we develop a Cas12b-mediated DNA detection (CDetection) strategy, which shows higher sensitivity on examined targets compared with the previously reported Cas12a-based detection platform. Moreover, we show that CDetection can distinguish differences at the single-base level upon combining the optimized tuned guide RNA (tgRNA). Therefore, our findings highlight the high sensitivity and accuracy of CDetection, which provides an efficient and highly practical platform for DNA detection.
Modulation of cytokine patterns and microbiome during pregnancy in IBD
Authors: Janine van der Giessen, Dana Binyamin, Anna Belogolovski, Sigal Frishman, Kinneret Tenenbaum-Gavish, Eran Hadar, Yoram Louzoun, Maikel Petrus Peppelenbosch, Christien Janneke van der Woude, Omry Koren, Gwenny Manel Fuhler
Journal: Gut (2019)

Objective Pregnancy may affect the disease course of IBD. Both pregnancy and IBD are associated with altered immunology and intestinal microbiology. However, to what extent immunological and microbial profiles are affected by pregnancy in patients with IBD remains unclear. Design Faecal and serum samples were collected from 46 IBD patients (31 Crohn’s disease (CD) and 15 UC) and 179 healthy controls during first, second and third trimester of pregnancy, and prepregnancy and postpartum for patients with IBD. Peripheral blood cytokine profiles were determined by ELISA, and microbiome analysis was performed by sequencing the V4 region of the bacterial 16S rRNA gene. Results Proinflammatory serum cytokine levels in patients with IBD decrease significantly on conception. Reduced interleukin (IL)-10 and IL-5 levels but increased IL-8 and interferon (IFN)γ levels compared with healthy controls were seen throughout pregnancy, but cytokine patterns remained stable during gestation. Microbial diversity in pregnant patients with IBD was reduced compared with that in healthy women, and significant differences existed between patients with UC and CD in early pregnancy. However, these microbial differences were no longer present during middle and late pregnancy. Dynamic modelling showed considerable interaction between cytokine and microbial composition. Conclusion Serum proinflammatory cytokine levels markedly improve on conception in pregnant patients with IBD, and intestinal microbiome diversity of patients with IBD normalises during middle and late pregnancy. We thus conclude that pregnancy is safe and even potentially beneficial for patients with IBD.
Immune-inflammatory and clinicopathologic prognostic factors in a Western cohort of resected gastric cancers (GCs)
Authors: M. Salati, S. Pipitone, M. Rimini, F. Gelsomino, A. Casadei Gardini, K. Andrikou, F. Schipilliti, G. Cortesi, L. Cassanelli, E. Caffari, F. Serra, A. Ricciardolo, N. De Ruvo, R. Gelmini, S. Cascinu, A. Spallanzani
Journal: Annals of Oncology (2019)
Identification of a nanostring signature that differentiates early pancreatic cancers according to stromal composition and predicts clinical outcome
Authors: F. Sclafani, L. Cascione, D. Cunningham, K. Young, P. Carotenuto, M. Fassan, M. Salati, A. Lanese, J. Berenguer Pina, K. Kouvelakis, I. Vendrell, I. Said-Huntingford, M. Previdi, R. Begum, A. Gillbanks, S. Hedayat, A. Sadanandam, A. Lampis, J. Hahne, N. Valeri, I. Chau, C. Braconi
Journal: Annals of Oncology (2019)
Gut–lung axis: discomfort, dysphagia and cough
Authors: Chen Chen Liu, Wu Cai
Journal: Thorax (2019)

Dysregulation of TNF is an important pathophysiological phenotype for many diseases. Recently, certain genetically regulated loci have been identified to regulate several inflammatory diseases. We hypothesized that a region on rat chromosome 4 known to regulate experimental autoimmune encephalomyelitis, experimental arthritis and experimental autoimmune neuritis harbors a gene regulating central inflammatory molecules, such as TNF. We therefore mapped TNF production using linkage analysis in the 12th generation of an advanced intercross line between DA and PVG.AV1 rats, which differ in susceptibility to several inflammatory conditions. A single TNF-regulating quantitative trait locus with a logarithm of odds score of 6.2 was identified and its biological effect was confirmed in a congenic rat strain. The profound TNF regulation mapped in congenic strains to the macrophage population. Several TLR signaling cascades led to the same reduced proinflammatory phenotype in congenic macrophages, indicating control of a convergence point for innate inflammatory activity. The decreased TNF potential and reduced proinflammatory macrophage phenotype in congenic rats was also associated with reduced clinical severity in experimental autoimmune encephalomyelitis, pristane-induced arthritis and sepsis experimental models. Determination of genes and mechanisms involved in this genetically determined TNF regulation will be valuable in understanding disease pathogenesis and aid treatment development.
Abstract 2375: Developing double knock-in models of human immune checkpoint targets (dKI HuGEMM) for efficacy assessment of combinatorial therapeutic antibodies
Authors: Lei Zheng, Daniel Xianfei He, Ruilin Sun, Annie Xiaoyu An, Jian Fei, Henry Qixiang Li, Davy Xuesong Ouyang
Journal: Cancer Research (2019)

Abstract Immune checkpoint inhibitors (ICIs), i.e. PD1, PDL1 and CTLA4 therapeutic antibodies, have led to long-term survival in many late stage solid tumor patients. Despite their revolutionary clinical impact, the overall response rate is still low. One major roadblock is that compensatory immune inhibitory pathways are turned on to protect tumor cells from being attacked by T cells. Various combinatory ICI treatments have now been investigated in clinical trials to tackle this challenge. We have previously reported the development of immune checkpoint target humanized mice (HuGEMM) through CRISPR-Cas9 knock-in. We have generated PD1 and CTLA4 HuGEMM mice and used them for efficacy assessment of corresponding therapeutic antibodies. We have also generated human PDL1 expressing MC38 cells and PDL1 HuGEMM, and demonstrated robust efficacy of several PDL1 therapeutic antibodies. Here we report the establishment of double knock-in (dKI) mice of ICI targets, i.e., PD1/PDL1 and PD1/CTLA4 dKI HuGEMM, and use them as tools to test immunotherapies with PD1/PDL1 and PD1/CTLA4 combos. Similar to clinical benefit of PD1 and CTLA4 combo shown in the melanoma and NSCLC patients, we found combined treatment of Nivolumab and Ipilimumab antibody leads to 103% TGI in the corresponding PD1/CTLA4 dKI-HuGEMM, with complete tumor remission in 80% of treated mice. These mice remained disease free throughout a tumor re-challenge study for over 40 days. We have also developed PD1/PDL1 dKI HuGEMM and tested combined treatment of Atezolizumab and Nivolumab. Interestingly, we observed improved efficacy in the combo treatment group despite the two ICIs are thought to target the same PD1/PDL1 axis. Monotherapies may not fully release the PD1/PDL1 blockade due to complicity of multiple compatible ligands &amp; receptors, including PDL2 and B7-1. We have also tested PD1/OX40 combo treatment with dKI HuGEMM, which is reported separately. Taken together, Our dKI HuGEMM models offer robust tests on ICI combinations, as well as combos of ICIs with other anti-tumor therapeutic modalities. Citation Format: Lei Zheng, Daniel Xianfei He, Ruilin Sun, Annie Xiaoyu An, Jian Fei, Henry Qixiang Li, Davy Xuesong Ouyang. Developing double knock-in models of human immune checkpoint targets (dKI HuGEMM) for efficacy assessment of combinatorial therapeutic antibodies [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 2375.