tbuckley/cabot-search huggingface dataset:
Abstract 5297: LCA: A robust and scalable algorithm to reveal subtle diversity in large-scale single-cell RNA-Seq data
Authors: Changde Cheng, John Easton, Celeste Rosencrance, Yan Li, Bensheng Ju, Wenan Chen, Xiang Chen
Journal: Cancer Research (2018)

Abstract Single-cell RNA sequencing (scRNA-seq) emerges as a powerful tool to characterize cell-to-cell variation and dynamics in a seemingly homogenous population. Efficient and affordable, scRNA-seq is gaining in popularity in both basic and translational biological research areas. However, significant challenges arise in the analysis of scRNA-seq data, including low signal-to-noise ratio with high data sparsity, rising scalability hurdles with hundreds of thousands of cells, and more. Due to inherent complexities in scRNA-seq data, the performance of currently available algorithms may not always be optimal even for fundamental tasks such as identifying heterogeneous subpopulations in the data. In this study, we developed Latent Cellular Analysis (LCA), a machine learning based analytical pipeline that combines similarity measurement by latent cellular states with a graph-based clustering algorithm. LCA features a dual-space model search for both the optimal number of subpopulations and the informative cellular states distinguishing them. LCA provides heuristic solutions for population number inference, dimension reduction, feature selection and confounding factor removal without explicit gene filtering. LCA has proved to be robust, accurate and powerful by comparison to multiple state-of-the-art computational methods on large-scale real and simulated scRNA-seq data. Importantly, LCA's ability to learn from representative subsets of the data provides scalability, thereby addressing a significant challenge for growing sample size in scRNA-seq data analysis. Citation Format: Changde Cheng, John Easton, Celeste Rosencrance, Yan Li, Bensheng Ju, Wenan Chen, Xiang Chen. LCA: A robust and scalable algorithm to reveal subtle diversity in large-scale single-cell RNA-Seq data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5297.
Abstract 4511: The role of Wnt5a signaling pathway in epithelial ovarian cancer progression
Authors: Marwa Asem, Allison Young, Carlysa Oyama, Rebecca Burkhalter, Steven Buechler, Daniel Miller, Sharon Stack
Journal: Cancer Research (2018)

Abstract Ovarian cancer (OvCa) is the most fatal gynecologic malignancy and the 5th leading cause of cancer death among U.S. women. The majority of women with OvCa (75%) have a very low survival rate (30%), as OvCa is usually diagnosed in late stages after development of intraperitoneal metastasis. Thus, it is indispensable to understand the molecular mechanisms that contribute to OvCa metastatic success, in order to design effective treatment strategies to improve the overall survival of women with OvCa. Wnt5a is a noncanonical Wnt ligand that binds to several cell membrane receptors and activates many downstream signaling pathways that are fundamental for normal developmental processes during embryogenesis. In the past decade, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor-suppressive effects. The role of Wnt5a in OvCa is controversial, as studies report conflicting data. In addition, mechanistic data regarding the contribution of Wnt5a to OvCa progression are largely unavailable. The main aim of this research is to obtain a molecular-level understanding of Wnt5a signaling in OvCa and to investigate its potential roles in influencing OvCa metastatic success. Our data show Wnt5a is prevalent in ascites samples from women in different stages with OvCa, suggesting a role for Wnt5a in promoting disease progression. Data obtained from TCGA (n=583) show high expression of Wnt5a in primary ovarian tumors. Furthermore, Wnt5a enhanced OvCa cells adhesion, migration and invasion in a panel of organotypic and ex vivo functional assays. This was combined with striking morphologic changes characteristic of an invasive phenotype in OvCa cells treated with recombinant Wnt5a protein and formation of tunneling nanotubes (TNT). Overall, our data suggest that Wnt5a plays an oncogenic role in epithelial ovarian cancer cells. More experiments exploring Wnt5a activated pathways and effects in epithelial ovarian cancer cells are under way. Citation Format: Marwa Asem, Allison Young, Carlysa Oyama, Rebecca Burkhalter, Steven Buechler, Daniel Miller, Sharon Stack. The role of Wnt5a signaling pathway in epithelial ovarian cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4511.
Abstract 14440: PI3Kα Deletion in Cardiomyocytes Causes Maintained Mitochondrial Membrane Potential and Blocks Necrotic Cell Death in Ischemia/Reperfusion Injury
Authors: Brent A McLean, Pavel Zhabyeyev, Xueyi Chen, Alois Haromy, Bart Vanhaesebroeck, Evangelos D Michelakis, Gavin Y Oudit
Journal: Circulation (2016)

Introduction: PI3K signaling is associated with protection in ischemia/reperfusion (IR) injury. However, PI3Kα dominant negative (PI3KαDN) with reduced PI3Kα in the heart has enhanced IR recovery. ...
Abstract 2828: MMR status affects efficiency of homologous recombination repair of F10-induced DNA DSBs
Authors: William H. Gmeiner, Chinnadurai Mani, Komaraiah Palle
Journal: Cancer Research (2018)

Abstract Background: DNA mismatch repair (MMR) is an important stratification factor in colorectal cancer (CRC). 10-20% of sporadic CRC cases display high microsatellite instability (MSI-H) due to DNA mismatch repair (MMR) deficiency, and these are refractory to current fluoropyrimidine (FP) chemotherapy. Our studies with DNA-directed FP polymers, such as F10, indicate they are highly effective regardless of MMR-deficiency consistent with inducing MMR-independent cell death. We investigate the role of MMR-status on potency of F10 and induction of DNA damage and activation of the DNA damage response as part of an overall effort to determine if fluoropyrimidine polymers can be used effectively in the treatment of MMR-deficient CRC. Methods: Studies were conducted using MMR-deficient HCT-116 CRC cells and HCT-116 3-6 cells. Potency was assessed by cell-titer glo and clonogenic assays. Replication stress was evaluated by DNA fiber combing. DNA damage and activation of the DNA damage response was evaluated by Western blots for gH2AX, Chk1 activation, and proteins important for homologous recombination repair. Results: F10 is highly potent to CRC cells regardless of MMR status and is ~1,000-fold more potent than 5-FU to MMR-deficient HCT-116 cells. The increased potency of F10 parallels increased efficiency at causing replication fork slowing as assessed by DNA fiber analysis. F10 causes DNA double strand breaks (DSBs) and activates Chk1 consistent with causing replication fork collapse. DNA DSBs, Chk1 activation, and upregulation of FANCD2, which mediates HR-repair of DNA DSBs all show a marked MMR-dependence consistent with hMLH1 being a factor in HR-mediated repair of F10-induced DNA DSBs. Conclusions: F10 is highly potent to CRC cells regardless of MMR status via a mechanism involving replication fork slowing and increased replication stress. MMR status affects basal levels of proteins involved in HR and the upregulation of these proteins in response to F10 treatment. Our studies indicate FP polymers are likely to be generally effective in CRC regardless of MMR status however MMR status may be an important factor in a personalized medicine approach to their use as combination with Chk1 inhibitors and other drugs modulating the DNA damage response may depend on MMR status. Citation Format: William H. Gmeiner, Chinnadurai Mani, Komaraiah Palle. MMR status affects efficiency of homologous recombination repair of F10-induced DNA DSBs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2828.
Abstract 2204: Influence of chronic comorbidities on colorectal cancer screening adherence in a population-based Canadian cohort
Authors: Dominika Bhatia, Rinku Sutradhar, Jill Tinmouth, Simron Singh, Lorraine Lipscombe
Journal: Cancer Research (2018)

Abstract Background: Regular screening for colorectal cancer (CRC) is associated with a lower stage at diagnosis and improved survival. National guidelines recommend periodic screening for adults aged 50-74 years. Chronic diseases may distract from regular screening and increase CRC burden. We sought to determine whether having certain chronic conditions is associated with a lower rate of CRC screening adherence. Methods: Using linked healthcare databases from Ontario, Canada, we assembled a population-based cohort of adults aged 50-74 years, who were eligible and overdue for routine CRC screening (fecal occult blood testing &amp;gt; 2 years, sigmoidoscopy &amp;gt; 5 years, or colonoscopy &amp;gt; 10 years) at any point between April 1, 2004 and March 31, 2016. We implemented Andersen-Gill extended Cox models for recurrent events using an age time scale to examine the impact of chronic conditions on the relative rate (RR, 95% confidence interval, CI) of becoming adherent with periodic CRC tests, adjusted for the relevant time-varying covariates. Results: During the 12-year observation window, included individuals contributed a total of 19,818,050 person-years spent overdue for CRC tests. Over 70% of all CRC tests performed during the study period were fecal occult blood tests. At baseline, of the 4,642,422 individuals that met the inclusion criteria, 31% had hypertension, 12% had diabetes, 9% had chronic obstructive pulmonary disease (COPD), 7% had mental illness, 5% had cardiovascular disease (CVD), 1.6% had congestive heart failure (CHF), and 0.1% had end-stage renal disease (ESRD). After adjustment for sociodemographic and health system factors, the highest rates of nonadherence were observed for ESRD on dialysis (RR 0.66, CI 0.63-0.68), CHF (RR 0.75, CI 0.75-0.76), COPD (RR 0.84, CI 0.83-0.84), CVD (RR 0.85, CI 0.84-0.85), diabetes (RR 0.86, CI 0.86-0.87), and mental illness (RR 0.88, CI 0.87-0.88). Hypertension (RR 0.98, CI 0.97-0.98) and ESRD with kidney transplant (RR 1.00, CI 0.84-1.19) were associated with modest to no risk. Conclusion: The presence of a major chronic condition is associated with lower adherence to CRC screening. Future studies should explore reasons for lower CRC screening adherence in individuals with chronic conditions and the appropriateness of secondary cancer prevention and early diagnosis in this population. Citation Format: Dominika Bhatia, Rinku Sutradhar, Jill Tinmouth, Simron Singh, Lorraine Lipscombe. Influence of chronic comorbidities on colorectal cancer screening adherence in a population-based Canadian cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2204.
Diverse Contribution of Bone Marrow–Derived Cells to Vascular Remodeling Associated With Pulmonary Arterial Hypertension and Arterial Neointimal Formation
Authors: MakotoSahara, MasatakaSata, ToshihiroMorita, KazutoNakamura, YasunobuHirata, RyozoNagai
Journal: Circulation (2007)

Background— Recent evidence suggests that bone marrow (BM)–derived cells may differentiate into vascular cells that participate in arterial repair and/or lesion formation. However, it remains uncertain whether BM-derived cells also can participate in vascular remodeling associated with pulmonary arterial hypertension. Methods and Results— The BM of Sprague-Dawley rats was reconstituted with that of green fluorescent protein–transgenic rats. The BM-chimeric rats were injected intraperitoneally with 60 mg/kg monocrotaline after unilateral subpneumonectomy, and they concurrently underwent wire-mediated endovascular injury in femoral artery. After 28 days, they had elevated right ventricular systolic pressure (58.8±5.4 versus 20.4±2.4 mm Hg in sham-control; P<0.01). The pulmonary arterioles were markedly thickened, with an infiltration of green fluorescent protein–positive macrophages into the perivascular areas. The endothelium of pulmonary arterioles contained only a few green fluorescent protein–positive c...
Abstract 2566: A TCL1-specific T-cell receptor redirects T cells against B-cell lymphomas and non-hematological tumors
Authors: Jinsheng Weng, Kelsey E. Moriarty, Yong Pan, Flavio Egidio Baio, Hua Wang, Hiroki Torikai, Sourindra N. Maiti, Fuliang Chu, Xiaoyun Cheng, Swathi Karri, Deepshika Medapalli, Laurence J. N. Cooper, Sattva S. Neelapu
Journal: Cancer Research (2018)

Abstract T-cell leukemia/lymphoma Antigen1 (TCL1) is a B-cell oncoprotein that is overexpressed in multiple forms of B-cell lymphoma. In our previous study, we identified a HLA*A0201-restricted T cell epitope from TCL1 that stimulated CD8+ T cells to specifically lyse lymphoma cells. In this study, we have cloned the TCL170-79 peptide-specific T-cell receptor (TCR) gene that after lentivirus transduction into donor T cells can redirect the specificity of T cells to lyse T2 cells pulsed with TCL170-79 but not control peptide. The TCR-transduced CD8+ T cells efficiently lysed HLA-0201+, TCL1-expressing human lymphoma cell lines and primary lymphoma cells, but not normal B cells. Adoptive transfer of TCR-transduced T cells into a mantle cell lymphoma xenograft mouse model inhibited the tumor growth and significantly extended the survival of mice. In addition, we found that TCL1 is expressed in multiple solid tumors. The TCR-transduced T cells lysed colon and liver tumor cells but not normal human cells in vitro as well as in a mouse xenograft model. Collectively, our data demonstrate that TCL1-specific TCR-based immunotherapy is highly effective against human B-cell lymphomas and non-hematological tumors. Citation Format: Jinsheng Weng, Kelsey E. Moriarty, Yong Pan, Flavio Egidio Baio, Hua Wang, Hiroki Torikai, Sourindra N. Maiti, Fuliang Chu, Xiaoyun Cheng, Swathi Karri, Deepshika Medapalli, Laurence J. N. Cooper, Sattva S. Neelapu. A TCL1-specific T-cell receptor redirects T cells against B-cell lymphomas and non-hematological tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2566.
Abstract 2082: High-throughput droplet digital PCR for MYCN amplification detection in FFPE neuroblastoma samples: Cost-effective, rapid, feasible, and reliable alternative to FISH
Authors: Dinesh Babu Somasundaram, Sheeja Aravindan, Zhongxin Yu, Muralidharan Jayaraman, Ngoc TB Tran, Shibo Li, Terence Herman, Natarajan Aravindan
Journal: Cancer Research (2018)

Abstract MYCN amplification directly correlates with the clinical course of neuroblastoma (NB) and poor patient survival, and serves as the most critical negative prognostic marker. Although FISH remains the gold standard for clinical diagnosis of MYCN status in NB, its limitations warrant the identification of rapid, reliable, less technically challenging, and inexpensive alternate approaches. In the present study, we examined the concordance of droplet digital PCR (ddPCR, in combination with IHC) with FISH for MYCN detection in FFPE NB samples. In 112 NB cases, ddPCR analysis demonstrated a 96-100% concordance with FISH. Consistently, IHC grading revealed 92-100% concordance with FISH. Comparing ddPCR with IHC, we observed a concordance of 95-98%. The results demonstrate that MYCN amplification status in NB cases can be assessed with ddPCR, and suggest that ddPCR could be a technically less challenging method of detecting MYCN status in FFPE specimens. More importantly, these findings illustrate the concordance between FISH and ddPCR in the detection of MYCN status. Together, the results suggest that rapid, less technically demanding, and inexpensive ddPCR in conjunction with IHC could serve as an alternate approach to detect MYCN status in NB cases, with near-identical sensitivity to that of FISH. Funding: NIH 1P20GM103639-01 from the COBRE Program of NIH; OUHSC Department of Radiation Oncology Research Development funds Citation Format: Dinesh Babu Somasundaram, Sheeja Aravindan, Zhongxin Yu, Muralidharan Jayaraman, Ngoc TB Tran, Shibo Li, Terence Herman, Natarajan Aravindan. High-throughput droplet digital PCR for MYCN amplification detection in FFPE neuroblastoma samples: Cost-effective, rapid, feasible, and reliable alternative to FISH [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2082.
Safety and immunogenicity of a pentavalent meningococcal conjugate vaccine containing serogroups A, C, Y, W, and X in healthy adults: a phase 1, single-centre, double-blind, randomised, controlled study
Authors: Wilbur H Chen, Kathleen M Neuzil, C Rebecca Boyce, Marcela F Pasetti, Mardi K Reymann, Lionel Martellet, Nancy Hosken, F Marc LaForce, Rajeev M Dhere, Sambhaji S Pisal, Amol Chaudhari, Prasad S Kulkarni, Ray Borrow, Helen Findlow, Valerie Brown, Megan L McDonough, Len Dally, Mark R Alderson
Journal: The Lancet Infectious Diseases (2018)
Abstract 3564: A combination of chimeric switch-receptor T cells targeting both PD1 and CTLA4 suppresses tumor growth
Authors: Peng Li, Le Qin, Xinru Wei, Ruocong Zhao, Yunxin Lai
Journal: Cancer Research (2018)

Abstract Chimeric antigen receptor (CAR) T cells have been successfully used to treat B cell malignancies, but faces many obstacles in solid tumors. A major challenge is the immune-suppressive effects induced by PD-L1 expression in tumors and CD80/86 that ligate with CTLA-4 and are expressed in myeloid-derived immune suppressive cells. Dual blockade of PD-1 and CTLA-4 with monoclonal antibodies has achieved promising anti-tumor effects in clinics. Here, we designed two switch receptor constructs. One contains the truncated extracellular domain of human PD1, costimulatory domains of 4-1BB and TLR2, and the CD3z signaling domain (cPD-1). cPD-1 T cells specifically lysed PD-L1+ tumor cell lines and augmented cytokine secretion in vitro. In addition, cPD-1 T cells were able to suppress the growth of lung cancer, gastric cancer, and osteosarcoma in xenografts. The other construct, similarly, is composed of the truncated extracellular domain of murine Ctla4, human CD28, TLR2, and CD3z signaling domains (cmCtla-4). Because CD80/CD86 are expressed in murine myeloid cells rather than human tumor cells in PDX models, cmCtla4 T cells targeted mouse myeloid cells that were abundant in tumors but not human tumor cells. We found that cmCtla4 T cells hindered tumor growth in gastric cancer PDX. In combination, cPD-1 and cmCtla4 T cells synergistically induced superior anti-tumor effects in lung cancer PDX. Taken together, our findings demonstrated the anti-tumor function of switched immune checkpoint receptors and revealed a strategy of combining T cells targeting both tumor cells and tumor microenvironment, promoting clinical investigation of these chimeric switch-receptor T cells for cancer treatment. Citation Format: Peng Li, Le Qin, Xinru Wei, Ruocong Zhao, Yunxin Lai. A combination of chimeric switch-receptor T cells targeting both PD1 and CTLA4 suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3564.
Abstract 5911: A bicistronic adenoviral vector carrying cytosine deaminase and GM-CSF genes significantly improves antitumor immunity and overall survival in colon cancer
Authors: Hakan Akbulut, Arzu Coleri, Gunce Sahin, Yucheng Tang, Albert Deisseroth, Fikri Icli
Journal: Cancer Research (2018)

Abstract Background: Combination of cytotoxic treatments with immunotherapeutic agents seem more efficacious than using either strategy alone. Oncolytic viral vectors carrying immunostimulatory genes like GM-CSF have emerged as treatment options in various tumors. Previously, we have shown that combination of suicide gene therapy either with GM-CSF or vector-induced dendritic cells has significant anti-tumor efficacy. In the current study, we aimed to combine the cytotoxic effect of the suicide gene cytosine deaminase and the immunostimulatory effect of granulocyte macrophage colony stimulating factor in a single vector construct. Methods: We have constructed a bicistronic adenoviral vector carrying cytosine deaminase (CD) and granulocyte macrophage-colony stimulating factor (GM-CSF) genes combined with an IRES element and driven by CMV promoter (Ad-CMV-CDiresGMCSF). We tested the in vitro efficacy of the vector in various tumor cell lines and in a mouse model of colon cancer. Results: Our bicistronic vector Ad-CMV-CDiresGMCSF showed significant in-vitro cytotoxic effects on tumor cell lines similar to the vector carrying CD gene alone when 5-FC added. Likewise, the GM-CSF producing efficacy of the bicistronic vector was comparable to the vector carrying GM-CSF gene alone. In the syngeneic colon cancer model, the bicistronic vector carrying CD and GM-CSF genes yielded significant tumor shrinkage and overall survival when compared to the control suicide vector carrying CD gene alone. Accordingly, anti-tumor immune response parameters including CTL assay and immune cell infiltration of tumor tissue were significantly improved in the Ad-CMV-CDiresGMCSF vector treated group (p&amp;lt;0.01). Conclusions: The Ad-CMV-CDiresGMCSF vector construct suggests a potential for the treatment of established tumors by inducing significant tumor killing and tumor-specific immune response. Citation Format: Hakan Akbulut, Arzu Coleri, Gunce Sahin, Yucheng Tang, Albert Deisseroth, Fikri Icli. A bicistronic adenoviral vector carrying cytosine deaminase and GM-CSF genes significantly improves antitumor immunity and overall survival in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5911.