tbuckley/cabot-search huggingface dataset:
Abstract 3580: GATK CNV: copy-number variation discovery from coverage data
Authors: Mehrtash Babadi, David I. Benjamin, Samuel K. Lee, Andrey Smirnov, Aaron Chevalier, Lee Lichtenstein, Valentin Ruano Rubio
Journal: Cancer Research (2017)

Abstract We propose and evaluate a novel algorithm for inferring germline and somatic copy number variation from whole exome sequencing (WES) and whole genome sequencing (WGS) data. Starting with the depth of aligned short reads from a cohort of samples, we use a Bayesian model for learning sequencing bias and simultaneously detecting CNV events using a hidden Markov model for change-point detection. A unified framework is used to call both germline and somatic CNVs. Denoising and event discovery are performed self-consistently to achieve maximum accuracy. In contrast to previous methods, our model naturally accounts for mixed sex cohorts and can detect events on sex chromosomes. Furthermore, we can detect excessively noisy samples and extract useful information within a probabilistic framework. Our implementation can also utilize Spark clusters, enabling the processing of larger cohorts and allowing for improved runtime performance. We benchmark the new method for precision, recall, and reproducibility of both germline and somatic variants. Evaluations are performed on a cohort of WES samples from The Cancer Genome Atlas with matching WGS data. For germline variants, we use blood normal samples and compare our calls on WES data against Genome STRiP calls on WGS data. We find that GATK CNV yields remarkably higher precision and recall compared to XHMM and CODEX software packages. For somatic variants, we compare our calls against TITAN and find a remarkably high concordance. Citation Format: Mehrtash Babadi, David I. Benjamin, Samuel K. Lee, Andrey Smirnov, Aaron Chevalier, Lee Lichtenstein, Valentin Ruano Rubio. GATK CNV: copy-number variation discovery from coverage data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3580. doi:10.1158/1538-7445.AM2017-3580
Abstract 219: Induced Pluripotent Stem Cells as a Potential Cell Source for Tissue Engineered Heart Valves
Authors: Aline L Yonezawa, Monalisa Singh, David Safranski, Kenneth M Dupont, Chunhui Xu, Michael E Davis
Journal: Circulation Research (2016)

Despite recent advances in tissue engineered heart valves (TEHV), one of the major challenges is finding a suitable cell source for seeding TEHV scaffolds. Native heart valves are durable because valve interstitial cells (VICs) maintain tissue homeostasis by synthesizing and remodeling the extracellular matrix. In this study, we demonstrate that induced pluripotent stem cells (iPSCs) can be derived into induced mesenchymal stem cells (iMSCs) using our feeder-free protocol and then further differentiated into VICs using a 3D cell culture environment. The differentiation efficiency was quantified using flow cytometry, immunohistochemistry staining, RT-PCR, and trilineage differentiation. In addition, iMSCs were encapsulated in polyethylene (glycol) diacrylate (PEGDA) hydrogels of varying stiffness, grafted with adhesion peptide (RGDS), to promote cell proliferation, remodeling, and further differentiation into VIC-like cells. VICs phenotype was characterized by the expression of αSMA, vimentin, F-actin, and the ECM production after 7, 14, and 21 days. The results demonstrated that using our feeder-free differentiation protocol, iMSCs were differentiated from iPSCs. Our iMSCs had a 99.9% and 99.4% positive expression for MSC markers CD90 and CD44, respectively. As expected, there was 0.019% expression of CD45, which is a hematopoietic marker. In addition, iMSCs differentiated into adipogenic, chondrogenic, and osteogenic. When MSC derived cells were encapsulated in PEGDA hydrogels that mimic the leaflet modulus, we observed expression of αSMA and F-actin after 7 days. Thus, the results from this study suggest that iPSCs can be a suitable cell source for TEHV by using a feeder-free differentiation approach and 3D culture.
Abstract 537: TRAF3 serves as a tumor suppressor in HPV-associated head and neck squamous cell carcinomas
Authors: Tony W. Chen, Jialing Zhang, Xinping Yang, Zhong Chen, Carter Van Waes
Journal: Cancer Research (2017)

Abstract The molecular mechanisms that control transformation and tumorigenicity of human papillomavirus-associated (HPV+) head and neck squamous cell carcinomas (HNSCCs) are currently being investigated. The number of HPV+ HNSCC cases has increased sharply in recent years, especially in tonsil and oropharyngeal cancers. These HPV+ HNSCCs often respond differently to treatments. Recently, The Cancer Genome Atlas (TCGA, 2015) identified novel loss-of-function genomic alterations of TNF receptor-associated factor 3 (TRAF3) in HPV+ HNSCCs. TRAF3 is a ring-finger E3 Ubiquitin Ligase which inhibits downstream alternative NF-κB signaling and promotes anti-viral immunity by promoting degradation of ubiquitinated proteins. To assess TRAF3’s role in HPV+ HNSCCs, we identified cell lines with lower level of TRAF3 protein, consistent with deficient TRAF3 expression identified in TCGA data. Functional studies showed that TRAF3 expression led to decreased steady-state protein levels of the alternative NF-κB pathway components RELB and NF-κB2/p52, as assessed by Western blot, reporter assays and immunofluorescence. Additionally, TRAF3 expression led to decreased cell proliferation, tumorigenic activity and migration, and increased sensitivity to chemotherapy agent cisplatin. Interestingly, TRAF3 increases the steady state protein level of the classical tumor suppressors RB and p53 in HPV+ HNSCC cell lines as assessed by Western blot. Further in vitro characterization of TRAF3’s function in HPV+ HNSCCs was assessed using clinically identified TRAF3 loss-of-function mutagenic isoforms, mimicking both TCGA data and HNSCC cell line data for TRAF3 defects. In contrast to wtTRAF3, these mutant forms of TRAF3 do not as strongly restore p53 or inhibit RELB and NF-κB2/p52 protein levels. One specific mutation which causes a frameshift at residue 210 greatly inhibits TRAF3 function as assessed by Western blot. To further assess effects of wt or TRAF3 loss-of-function mutants in vitro and in vivo, an inducible HPV+ HNSCC line expressing TRAF3 using the TET-ON system, and TRAF3 knockout in HPV+ HNSCC line and Human Oral Keratinocyte (HOK) line using CRISPR-Cas9 genomic editing are generated. In conclusion, the ring-finger E3 ubiquitin ligase TRAF3 inhibits the pro-survival alternative NF-κB signaling pathway and restores TP53 and RB, thereby serving as a tumor suppressor in HPV+ HNSCCs. (Supported by NIDCD intramural project ZIA-DC-000016, 73 and 74) Citation Format: Tony W. Chen, Jialing Zhang, Xinping Yang, Zhong Chen, Carter Van Waes. TRAF3 serves as a tumor suppressor in HPV-associated head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 537. doi:10.1158/1538-7445.AM2017-537
Abstract 1061: Modulation of death pathways by TRAILR2 agonist antibody and NF-κB pathway by NIK inhibitor in HPV-positive head and neck squamous cell carcinomas
Authors: Yi An, Lillian Sun, Adeeb Derakhshan, Sophie Carlson, Rita Das, Zhong Chen, Carter Van Waes
Journal: Cancer Research (2017)

Abstract Head and neck squamous cell carcinomas (HNSCC) induced by human papilloma virus (HPV) have increased recently in the US, and exhibit a different prognosis and response to therapies from HPV(-) cancers. Analysis of HNSCC TCGA datasets provide evidence for distinct alterations in expression of components of the NF-κB and death pathways in HNSCC with different HPV status. Previously, we have found that birinipant, a novel SMAC mimetic that inhibits inhibitor of apoptosis proteins (IAPs), sensitizes a subset of HPV(-) HNSCC cell lines to death agonists like TNF-α and TRAIL. In this study, we have observed that birinipant also sensitizes most HPV(+) cell lines to TRAIL and TNF-α in vitro. The IC50 of birinipant was under 50nM for HPV(+) UPCI-SCC-90 and UM-SCC-47 cell lines, when combined with TNF-α or TRAIL. To explore the therapeutic potential of enhancing TRAILR mediated death signaling in HPV(+) HNSCC cells, we investigated the effects of an agonistic polyclonal TRAILR2 antibody. Treatment of cells with TRAILR2 antibody alone shows little or no inhibitory effect on UPCI-SCC-90 and UM-SCC-47 cells in vitro. However, a combination of birinipant and TRAILR2 antibody, or triple combination of birinipant, TRAIL, and TRAILR2 antibody shows additive or synergistic effects to inhibit cell proliferation and induce cell death in a dose dependent manner. In addition, our preliminary data suggested that the non-canonical NF-κB pathway is predominately activated in HPV(+) HNSCC cells, and that NF-κB inducing kinase (NIK) is a key component of this pathway. When we tested the NIK inhibitor 4H-isoquinoline-1,3-dione in UPCI-SCC-90 cells, we found it reduced cell proliferation in a dose-dependent manner (IC50 =1.5 μM). Taken together, these results indicate that TNF-α, TRAIL, and TRAILR2 agonist antibody sensitized birinipant anti-tumor activity, and triple combination exhibited synergistic effects in HPV(+) HNSCC cell lines. NIK inhibitor alone inhibits cell proliferation of HPV(+) cells, supporting the hypothesis of aberrant activation of alternative pathway in HPV(+) HNSCC cells. (Supported by NIDCD intramural projects ZIA-DC-000016, 73, 74). Citation Format: Yi An, Lillian Sun, Adeeb Derakhshan, Sophie Carlson, Rita Das, Zhong Chen, Carter Van Waes. Modulation of death pathways by TRAILR2 agonist antibody and NF-κB pathway by NIK inhibitor in HPV-positive head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1061. doi:10.1158/1538-7445.AM2017-1061
Relative Resistance to Penicillin in the Pneumococcus
Authors: Alfred J. Saah
Journal: JAMA (1980)

Isolates of<i>Streptococcus pneumoniae</i>from 103 patients were submitted for serotyping and determination of the minimum inhibitory concentration (MIC) for penicillin. Isolates from 16 patients were relatively resistant to penicillin (MIC, 0.1 to 0.5 μg/ML). In a study to determine if the patients with relatively resistant pneumococci (RRP) differed from patients with normally susceptible pneumococci, 18 patients with RRP showed no significant difference from their matched controls in antibiotic use during the two months prior to isolation of the pneumococcus. Other variables that showed no significant difference between the two groups were (1) antibiotic use in household contacts in the previous six months, (2) presence of chronic infection in the case or control patient, and (3) recurrence of pneumococcal infection following therapy. The high rate of relative resistance to penicillin is heretofore unknown in a general, unconfined population in this country. The case-control study suggests that no strong relationship exists between isolating RRP and prior penicillin administration. More extensive surveys in the United States are needed. (<i>JAMA</i>243:1824-1827, 1980)
Abstract 5703: An ultra-sensitive multiplex allele-specific real-time PCR (Udx-PCR) assay for detection ofESR1mutations in metastatic breast cancer
Authors: Jiasu Liu, Yaohuai Wang, Shengrong Sun, Dehua Derek Yu
Journal: Cancer Research (2017)

Abstract Activating mutations of estrogen receptor α (ESR1) are attributed to acquired resistance to estrogen-deprivation therapy in patients with metastatic breast cancer (MBC). Thus, detection of these mutations is clinically critical for monitoring early progression and effective therapeutic options in treatment of BC patients under hormonal therapy. However, current investigations for detection ESR1 mutations mainly focus on digital PCR technology due to low abundance of the cfDNA in plasma samples, which is not a currently feasible method for clinical diagnosis. Herein, we developed a multiplex allele-specific real-time (ARMS) PCR assay for detection of ESR1 four mutations (Y537S, Y537C, Y537N, and D538G) in a single tube reaction. In this real-time PCR system, the wild-type ESR1 DNA is completely blocked by a modified probe with a higher annealing temperature, and the mutant gene is selectively amplified by the modified ARMS primers. The assay was found to be highly specific and sensitive. With this assay, as low as 0.1% mutant DNA template in the background of a total of 10ng wild-type genomic DNA could be detected. By using this assay, we analyzed the ESR1 mutations in 50 Chinese MBC FFPE and plasma samples. The ESR1 mutations were detected in 3 FFPE and 6 plasma samples, which were confirmed by pyrophosphate sequencing. The multiplex allele-specific real-time PCR assay provides a rapid and reliable diagnostic tool for accurate detection of ESR1 mutations with potential for clinical application. Citation Format: Jiasu Liu, Yaohuai Wang, Shengrong Sun, Dehua Derek Yu. An ultra-sensitive multiplex allele-specific real-time PCR (Udx-PCR) assay for detection of ESR1 mutations in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5703. doi:10.1158/1538-7445.AM2017-5703
Abstract 3662: Activation of CD40 while inhibiting IL6/STAT3 using oncolytic viruses induces mature DCs with high cytokine production but blocks PDL1 expression
Authors: Emma Eriksson, Ioanna Milenova, Jessica Wenthe, Anna Dimberg, Rafael Moreno, Gustav Ullenhag, Ramon Alemany, Angelica Loskog
Journal: Cancer Research (2017)

Abstract The tumor microenvironment (TME) consists of tumor cells and stroma, including fibroblasts, blood vessels, immune cells and extracellular matrix. The TME supports tumor progression, metastasis as well as resistance to cancer therapeutics. In pancreatic cancer, the TME is dense due to overproduction of collagen and the tumor is infiltrated with suppressive myeloid cells such as M2 macrophages and myeloid suppressor cells. One key regulator of myeloid cells is CD40, a receptor expressed on a variety of cell types. CD40/CD40L signaling results in production of cytokines and chemokines by myeloid cells but also endothelial and epithelial cells to alert the immune system of immediate danger. 4-1BB is expressed by lymphocytes and dendritic cells (DCs). Stimulation via 4-1BBL drives lymphocyte expansion and regulates memory formation. IL6 signaling leads to STAT3 phosphorylation in myeloid cells and tumor cells leading to suppressive phenotypes, tumor proliferation, and angiogenesis. Further, STAT3 signaling enhances production of TGFb, which in turn leads to overexpression of collagen. We have constructed a family of oncolytic adenoviruses (LOAd) activating the CD40, 4-1BB and/or inhibiting IL6 signaling. The LOAd viruses (-, 700, 703, 713) were investigated for their capacity to activate human monocyte-derived DCs as well as their effect on pancreatic tumor cells and stroma (fibroblastic stellate cells, endothelial cells) using flow cytometry, MTS assay and ProSeek Proteomics. The LOAd viruses expressing a trimerized CD40L, 4-1BBL and/or a scFv IL6R showed efficient oncolysis of tumor cells but primary stellate cells were unaffected. However, stellate cells reduced tumor-promoting factors such as FGF5, PlGF, amphiregulin, Gal3, TGFb and collagen type I. Dendritic cells increased costimulators, cytokines as well as chemokines but PDL1 was not expressed when IL6/STAT3 was blocked. Infected endothelial cells upregulated receptors important for lymphocyte transmigration (ICAM, VCAM and E-Selectin). Taken together, our data demonstrates that it is possible to utilize oncolytic adenoviruses to spark immune activation at the same time changing biological processes via STAT3 blockade and/or CD40/4-1BB pathway activation to reduce factors that promotes tumor progression. Citation Format: Emma Eriksson, Ioanna Milenova, Jessica Wenthe, Anna Dimberg, Rafael Moreno, Gustav Ullenhag, Ramon Alemany, Angelica Loskog. Activation of CD40 while inhibiting IL6/STAT3 using oncolytic viruses induces mature DCs with high cytokine production but blocks PDL1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3662. doi:10.1158/1538-7445.AM2017-3662
Abstract 2166: Arsenic trioxide targets BCL6 oncoprotein for degradation in BCL6-dependent diffuse large B-cell lymphoma
Authors: Lok Man Yue, David Hau Wing Chau, Wenying Piao, (Eric) Wai Choi Tse, Yok Lam Kwong
Journal: Cancer Research (2017)

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma throughout the world. B-cell lymphoma 6 (BCL6) overexpression is frequently observed in DLBCL. Several recent studies have supported that BCL6 is a critical pathogenic oncoprotein in DLBCL. BCL6 represses various downstream genes, including ATR, TP53 and CDKN1A, thereby impairing DNA repair leading to derangement of cellular proliferation. Most importantly, a specific small molecule inhibitor targeting BCL6 successfully suppressed growth of BCL6-dependent DLBCL cell lines and primary human DLBCL cells, further suggesting that BCL6 plays an important pathogenetic role. Arsenic trioxide (As2O3) has been reported to target various oncogenic proteins, including PML-RARA in acute promyelocytic leukemia, cyclin D1 in mantle cell lymphoma, NPMc+ in acute myeloid leukemia and NPM-ALK in anaplastic large cell lymphoma, for degradation through ubiquitin-proteasome pathway. In this study, we investigated the effects of As2O3 on BCL6 in DLBCL. As2O3 was found to inhibit cell proliferation and induce cell death via apoptosis in DLBCL cells. More interestingly, BCL6-dependent DLBCL cells were found to show higher sensitivity towards As2O3-induced cytotoxicity. BCL6 was found to be degraded by As2O3 at posttranslational level through the ubiquitin-proteasome pathway. Such degradation led to an upregulation of several downstream targets of BCL6, including PRDM1, CD44 and CD69. Moreover, As2O3 synergized with cisplatin to inhibit cell proliferation and enhance apoptosis in BCL6-dependent DLBCL cell lines. Concomitant treatment with As2O3 and cisplatin further enhanced the phosphorylation of Chk1 and γH2AX in these cells. In conclusion, our data suggest that As2O3 is a potential therapeutic agent for the treatment of BCL6-dependent DLBCL. On top of that, new combination therapies can be developed to expand the therapeutic spectrum of As2O3 to other neoplasms. Citation Format: Lok Man Yue, David Hau Wing Chau, Wenying Piao, (Eric) Wai Choi Tse, Yok Lam Kwong. Arsenic trioxide targets BCL6 oncoprotein for degradation in BCL6-dependent diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2166. doi:10.1158/1538-7445.AM2017-2166
Abstract 4755: Calpastatin phosphorylation regulates radiation response in glioblastoma
Authors: Emily A. Bassett, Mitchell Pearson, Kamalakannan Palanichamy, Saikh J. Haque, Arnab Chakravarti
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is the most prevalent and aggressive primary malignant brain tumor in adults. Patients diagnosed with GBM have a very poor prognosis and quality of life, with a median survival time of 12-15 months despite receiving the standard of care treatment. GBMs are highly heterogeneous, invasive, and resistant to both chemo- and radio-therapy. The overall goal of this study is to identify novel mechanisms of radioresistance in GBM, so that more effective therapies can be developed in the future. We performed quantitative mass spectrometry-based phosphoproteomic profiling of GBM cell lines before and after radiation treatment, and determined post-radiation fold-changes in phosphorylation for each phosphopeptide. Results show calpastatin as one of the statistically significant differentially regulated phosphopeptides following radiation treatment. Calpastatin is an endogenous inhibitor of calpains, which are calcium-dependent cysteine proteases that control a wide range of cellular processes including cell survival and apoptosis. We hypothesized that phosphorylation inactivates calpastatin resulting in increased calpain activity. Western blot analyses with phospho-specific calpastatin antibodies validated the mass spectrometry results. In order to test the functional significance of phosphorylated calpastatin, we utilized site-directed mutagenesis to generate non-phosphorylatable and phospho-mimetic calpastatin proteins. Western blot analyses of U87 cells stably expressing CAST-S633A or -S633E supported the hypothesis that calpastatin phosphorylation leads to increased calpain activity. In conclusion, we identified increased levels of calpastatin phosphorylation in multiple GBM cell lines following radiation treatment, and shown that this correlates with increased calpain activity. Modulation of calpastatin activity is a potential strategy to increase radiosensitivity of glioblastomas. Targeting calpastatin is advantageous over targeting calpain itself, since many calpain inhibitors exhibit limited selectivity. Results of this study will contribute to our understanding of how GBM tumors become resistant to radiation therapy. Funding: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and The Ohio State University CCC (all to AC). Citation Format: Emily A. Bassett, Mitchell Pearson, Kamalakannan Palanichamy, Saikh J. Haque, Arnab Chakravarti. Calpastatin phosphorylation regulates radiation response in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4755. doi:10.1158/1538-7445.AM2017-4755
Abstract 5943: Role of tissue stiffness and oxygen tension in promoting breast cancer stem cells
Authors: Mei-Fong Pang, Derek C. Radisky, Celeste M. Nelson
Journal: Cancer Research (2017)

Abstract Breast tumors are stiff and hypoxic. Nevertheless, it remains unclear how stiff and hypoxic conditions within the tumor microenvironment promote breast cancer progression. Using an innovative engineered culture model to recapitulate these features, we found that, under stiff and hypoxic conditions, breast cancer cells have enhanced integrin-linked kinase (ILK) expression and acquire cancer stem cell (CSC)-like traits, suggesting tissue stiffness and oxygen tension can modulate ILK expression to induce breast CSC formation. Knocking down ILK impairs the mechanosensing of invasive breast cancer cells on stiff microenvironments, inhibits CSC markers and properties. In contrast, ectopic expression of ILK promotes breast CSC formation. In addition to promoting CSC-like phenotype, microarray analysis reveals that stiff and hypoxic microenvironments also regulate genes involved in mRNA processing, splicing and the spliceosome. These data suggest that the non-cellular compartment of the tumor microenvironment, namely tissue mechanics and oxygen tension, can promote breast cancer progression by controlling mechanotransduction and post-transcriptional regulation of breast cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Mei-Fong Pang, Derek C. Radisky, Celeste M. Nelson. Role of tissue stiffness and oxygen tension in promoting breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5943. doi:10.1158/1538-7445.AM2017-5943