bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 485: The NCI Mouse Repository: Cancer models and microRNA ES cell resource
Authors: Awasthi Parirokh , Fitzgerald Debra , Jones Stephen 
Published: September 2020

Abstract
The NCI Mouse Repository, located at the Frederick National Laboratory for Cancer Research (FNLCR), Frederick, Maryland, is an NCI-funded resource of approximately 150 genetically-engineered mouse cancer models and associated strains, including mice bearing conditional and point-mutant alleles in cancer-related genes. In addition, the Repository houses a unique collection of over 1500 different mouse ES cell clones bearing conditionally-activated miRNA transgenes to facilitate in vivo exploration of miRNA functions. The NCI Mouse Repository makes strains and mESCs available to all members of the scientific community (academic, non-profit, and commercial). The mouse models and ES cell clones are cryo-archived and distributed as frozen germplasm or cells.
Requests may be placed through the NCI Mouse Repository website (https://ncifrederick.cancer.gov/Lasp/MouseRepository/Default.aspx). In addition to the request form, this website includes detailed description for each strain accepted into the Repository and the associated publications provided by the donating scientist. The miR-harboring ESCs, originally generated at the Cold Spring Harbor Laboratories for the NCI, are described in full detail and include validation data for each miRNA ES cell clone. These resources are available for nominal cost to NCI, NIH, and other US government-funded investigators, as well as to Investigators at non-profit organizations.
Citation Format: Parirokh Awasthi, Debra Fitzgerald, Stephen Jones. The NCI Mouse Repository: Cancer models and microRNA ES cell resource [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 485.
Abstract 4872: Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53
Authors: De Pradip K. , Aske Jennifer C. , Costello Joseph P. , Thompson Ethan , Dey Nandini 
Published: September 2020

Abstract
Background: Apoptosis is the therapeutic goal following the administration of anti-cancer drugs. BCL2 and p53 are two important nodes in the apoptosis signaling pathway. Previous reports have shown that the anti-apoptotic protein BCL2 and p53 degrader MDM2 are overexpressed in many solid neoplasms, including ovarian cancers, and associated with poor clinical outcome.
Purpose: Since monotherapy in cancer is generally not providing long-lasting clinical responses, here, we hypothesize that concomitant p53 activation (by an inhibitor of MDM2-p53 interaction, e.g. AMG232) and BCL2 inhibition (by venetoclax) induce maximum apoptosis and markedly reduce tumor cell proliferation in ovarian clear cell and endometrioid carcinomas with wild type (WT) TP53.
Methods: We tested the anti-proliferative and apoptotic activity of venetoclax (V) alone, AMG 232 alone (A), and a combination of V plus A in ovarian clear cell carcinoma (OVISE cells) and ovarian endometrioid carcinoma cell lines (A2780 & isogenic Cisplatin resistant A2780CisR).
Results: 1) A binds the MDM2 protein, blocks MDM2-p53 interaction, and induces p53 expression and activity, 2) p53 effector molecule p21 is robustly induced following the treatment of A, 3) the anti-proliferative activity of V or A was observed by 3D-ON-TOP clonogenic assay and real-time monitoring in an IncuCyte Zoom, 4) all three cell lines exhibited an increase in annexin V positivity (initiation of apoptotic activity) following V or A treatment, 5) importantly, a combination of V plus A robustly induced the apoptotic markers e.g. cleaved-CASPASE3/7, cleaved PARP1 and BIM protein expression in all cell lines, 6) high mitochondrial depolarization was also observed following the combination of treatment, 7) similar to protein expression data, mRNA data also showed that pro-apoptotic/cell cycle inhibitor transcripts such as p21 and PUMA mRNA expression were significantly increased and 8) normoxic HIF1α degradation is not rescued following the treatment of MDM2-p53 interacting inhibitor A however A-induced p53 activation inhibits hypoxic HIF1α accumulation.
Conclusion: These data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy for ovarian clear cell and endometrioid carcinomas patients that retain WT-TP53.
Citation Format: Pradip K. De, Jennifer C. Aske, Joseph P. Costello, Ethan Thompson, Nandini Dey. Therapeutic value of BCL2 and MDM2-p53 axis in ovarian clear cell and endometrioid carcinomas with wild type TP53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4872.
Abstract 4893: Multi-modality sequencing of multiple HPV mediated oropharyngeal squamous cell carcinomas from single patients reveals synchrony in viral genomes yet discordant mutational profiles and signatures
Authors: Faden Daniel L. , Langenbucher Adam , Kuhs Krystle , Lewis James S. , Lawrence Michael S. , Mirabello Lisa , Ferris Robert L. 
Published: September 2020

Abstract
Human Papilloma Virus (HPV) mediated oropharyngeal squamous cell carcinoma (HPVmOPSCC) is increasing in prevalence in the United States, as are cases of patients with multiple, spatially distinct, HPVmOPSCCs (mHPVmOPSCC). Patients with mHPVmOPSCCs present a unique opportunity to study the biology of HPV mediated tumorigenesis in the oropharynx, which currently is poorly understood. We performed whole exome sequencing and RNA-Seq on 16 paired HPVmOPSCCs (eight patients) and whole genome sequencing of the viral genome using a HPV16 NGS assay described previously. Viral sequencing revealed considerable diversity between patients, across multiple viral sublineages. However, all tumor pairs from a given patient contained the same viral genome, with at most 2 clonal SNPs distinguishing the viruses within a pair. In contrast, tumor DNA sequencing revealed striking dissimilarity between tumors from a given patient. Seven of eight tumor pairs shared no overlapping somatic mutations with one pair sharing only six variants out of 277 (2%). Mutational signature analysis demonstrated a dominant APOBEC signature in six tumors. Tumor pairs showed striking discordance of mutational signatures. In 3/8 pairs, one tumor exhibited a nearly 100% pure APOBEC+ mutational profile, while the other was totally devoid of APOBEC-signature mutations. Here, we have demonstrated that spatially independent tumors, originating within the same individual, in the same tissue type, are caused by the same virus. Interesting, despite this shared etiology, the pair of tumors within a patient develop with vastly different mutational profiles and have different mutational processes driving tumorigenesis. This suggests that despite infection by a single oncogenic virus, HPVmOPSCCs may develop via multiple, disparate pathways. Of particular interest is the tumor pairs' clear discordance in APOBEC mutational burden, which challenges existing hypotheses on the role of APOBEC mutagenesis in this disease.
Citation Format: Daniel L. Faden, Adam Langenbucher, Krystle Kuhs, James S. Lewis, Michael S. Lawrence, Lisa Mirabello, Robert L. Ferris. Multi-modality sequencing of multiple HPV mediated oropharyngeal squamous cell carcinomas from single patients reveals synchrony in viral genomes yet discordant mutational profiles and signatures [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4893.
Abstract 4911: Characterizing the role of podocalyxin's cytoplasmic tail domain in collective tumor invasion
Authors: Bell Erin M. , Graves Marcia L. , Dean Pamela , McNagny Kelly M. , Roskelley Calvin D. 
Published: September 2020

Abstract
High expression of the single-pass transmembrane sialomucin, podocalyxin, has been shown by many groups to correlate with poor disease outcome in a number of solid tumor types, including colorectal, ovarian, pancreatic and breast cancers. We had previously identified that high podocalyxin expression in invasive ductal breast carcinoma was an independent indicator of poor survival (Somasiri et al., 2004, Cancer Res. 64:15). Further analysis of these tumor samples revealed that this decrease in survival occurred without the loss of membranous, junctional E-cadherin, suggesting that these tumors may have invaded collectively without necessitating an overt epithelial to mesenchymal transition (EMT). Experimentally, forced over-expression of podocalyxin in polarity-disrupted human MCF7 breast cancer cells drives the formation of invasive orthotopic xenograft tumors and elongated, cohesive, and E-Cadherin-expressing spheroids in three-dimensional (3D) culture as compared to control (Graves et al., 2016, Breast Canc. Res. 18:11). Further, treatment of these podocalyxin-overexpressing MCF7 cells with the myosin inhibitor, blebbistatin, and the small molecule inhibitor of ezrin-actin binding, NSC668394, resulted in decreased collective invasion and migration, respectively. Together these data suggest that podocalyxin, through interactions with the actin cytoskeleton via its cytoplasmic tail binding partners, can facilitate increased collective epithelial tumor cell motility, at least in some contexts. To test this hypothesis, we generated podocalyxin null MCF7 clones and cell populations using CRISPR-Cas9 genome editing and reconstituted these cells with mutant forms of podocalyxin that are unable to interact with the scaffolding proteins NHERF and/or ezrin and hence with the actin cytoskeleton. Preliminary results from 3D culture and live imaging of these mutant podocalyxin-expressing cells suggests that loss of podocalyxin's cytoplasmic tail results in decreased spheroid invasion that may be a result of deficiencies in actomyosin contractility. Hence, increased expression and mislocalization of podocalyxin may facilitate aberrant interactions with the actin cytoskeleton and contractile machinery, driving enhanced cell motility and, in certain tumor microenvironments, promote collective tumor invasion.
Citation Format: Erin M. Bell, Marcia L. Graves, Pamela Dean, Kelly M. McNagny, Calvin D. Roskelley. Characterizing the role of podocalyxin's cytoplasmic tail domain in collective tumor invasion [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4911.
Abstract 4943: The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic pontine glioma
Authors: Guo Huizi , Kaur Harpreet , Eberhart Charles G. , Raabe Eric H. 
Published: September 2020

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. With radiation therapy as the primary treatment, the median survival after diagnosis is 6 months. Identifying molecular markers that regulate tumor growth is urgently needed to develop targeted therapies. LIN28B is a stem cell factor expressed during normal neural development and re-expressed in cancer cells. In many cancers, LIN28B acts as an RNA-binding protein and downregulates the tumor-suppressing let-7 microRNAs. We had previously shown that LIN28A, a homolog of LIN28B, regulates invasion and tumorigenicity in adult high-grade gliomas. LIN28B is known to be highly expressed in DIPG. Thus, we hypothesized that LIN28B would be important in DIPG by promoting tumor growth. We observed that LIN28B was expressed in patient-derived DIPG cell lines (JHHDIPG1, JHHDIPG16A, SUDIPGXIII, HSJD-007, SF7761). Knockdown of LIN28B using short hairpin RNAs decreased DIPG cell proliferation (BrdU incorporation) between 50% to 90% (p&lt;0.01). The knockdown of LIN28B also increased DIPG cell apoptosis (cleaved caspase-3 and cleaved PARP expression) by 2- to 3-fold (p&lt;0.01). To determine the molecular mechanism of LIN28B-mediated phenotypes in DIPG, we studied canonical downstream effectors of LIN28B. We found that when LIN28B was suppressed in DIPG cells, there was a decreased expression of the DNA-binding oncoprotein called high mobility group AT-hook 2. These findings suggest that LIN28B could be a potential therapeutic target for this devastating pediatric brain tumor. Future studies will focus on validating the role of LIN28B in DIPG growth in vivo using orthotopic zebrafish and mouse models.
Citation Format: Huizi Guo, Harpreet Kaur, Charles G. Eberhart, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4943.
Abstract 4963: Notch1 non-canonical pathway drives breast cancer stem cell function
Authors: Sui Lufei , Wang Suming , Sim Danielle , Watnick Randolph S. 
Published: September 2020

Abstract
Current treatment of triple negative breast cancer is hindered by a high incidence of chemoresistance (30-50%). The prevailing theory is that resistance and subsequent recurrence is driven by cancer stem cells. Unfortunately, the functional characterization of cancer stem cells at the molecular level is still incomplete. We show here, that within the canonical breast cancer stem cell population (CD24low/CD44+/ESA+) of triple negative breast cancer cells, a subset of cells characterized by high Notch1 expression possesses the tumor-initiating and chemoresistance properties associated with cancer stem cells. Moreover, the tumor initiating property of these Notch1-high expressing breast cancer stem cells is mediated by the repression of SIRT1. We also demonstrate that Notch1 represses SIRT1 through a non-canonical, cleavage independent pathway via PI3K/Akt/mTORC2. Strikingly, the repression of SIRT1 obviates the requirement for high Notch1 expression. These findings provide the first functional mechanistic requirements for breast cancer stem cell tumor initiation and chemoresistance. Our results also identify a novel non-canonical Notch1 signaling pathway regulating breast cancer stem cell function. We postulate that this pathway can be exploited as a potential therapeutic strategy to eradicate cancer stem cells and reduce the incidence of chemoresistance and recurrence.
Citation Format: Lufei Sui, Suming Wang, Danielle Sim, Randolph S. Watnick. Notch1 non-canonical pathway drives breast cancer stem cell function [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4963.
Abstract 4966: MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization in mice
Authors: Zhang Jinhua , Tian Tian , Yuan Qi 
Published: September 2020

Abstract
Background & Aims: The signal adapter MyD88, an essential component of TLR signaling, plays an important role in gut-microbiome interactions. However, its contribution to colitis-associated cancer (CAC) is still controversial. We investigated whether MyD88 signaling in myofibroblasts contributes to an environment that promotes CAC development.
Methods: C57BL/6J mice (control) and mice with myofibroblasts-specific deletion of MyD88 (Fib-MyD88 KO) were performed azoxymethane (AOM)/dextran sodium sulfate (DSS) model or DSS model. Colon tissue was collected and analyzed for inflammation, cell proliferation and macrophage polarization. Primary normal fibroblasts (NFs) were isolated and measured for mechanisms that induced macrophage polarization.
Results: Myofibroblasts MyD88-deficient mice were resistant to AOM/DSS-induced tumorigenesis, as evidence by the decrease in the number and sizes of tumors. MyD88 deficiency in myofibroblasts did not affect the inflammatory response but attenuated intestinal epithelial cell (IEC) proliferation after acute DSS-induced colitis. Furthermore, MyD88 signaling in myofibroblasts increased the secretion of osteopontin (OPN), which promoted macrophage M2 polarization through binding to αvβ3 and CD44, leading to activation of the STAT3 and PPARγ pathways.
Conclusions: MyD88 signaling in myofibroblasts crucially contributes to colorectal cancer development and provides a promising therapeutic target for the prevention of colitis-associated carcinogenesis.
Citation Format: Jinhua Zhang, Tian Tian, Qi Yuan. MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4966.
Abstract 4970: Prognostic role of CD112R, PD-1 and Ki67 expression in CD8+cytotoxic T cells in colorectal cancer
Authors: Simon Ronald , Blessin Niclas Christian , Mandelkow Tim , Bady Elena , Hube-Magg Claudia , Sauter Guido , Lennartz Maximilian , Fraune Christoph , Weidemann Sören A. , Möller Katharina , Büscheck Franziska 
Published: September 2020

Abstract
Expression of inhibitory immune checkpoint receptors such as CD112R (Poliovirus Receptor-Related Immunoglobulin Domain-Containing Protein, PVRIG) and PD-1 on CD8+ lymphocytes are considered to indicate an “exhausted” stage of T cell activation while Ki67 protein expression in these cells is viewed as sign of activity or expansion. To assess the prognostic impact of the clinical impact of CD112R, PD-1, and Ki67 expression of CD8+ lymphocytes, expression of these proteins was analyzed by fluorescent multiplex immunohistochemistry on a tissue microarray containing 384 colorectal cancers with clinical follow-up data. An elevated fraction of CD8+Ki67+ cells was linked to the absence of nodal metastasis and longer survival in these tumors (p≤0.0039 each). CD112R and PD-1 expression was detected at variable intensity levels and were separately quantitated in both ki67+ (expanding) and Ki67 negative (non-expanding) CD8+ cytotoxic lymphocytes. Elevated PD-1 expression in CD8+ T cells was associated with an absence of nodal metastasis (p=0.004) and longer overall survival in all CD8+ cells (p=0.005). This association was more evident in the subset of expanding (p&lt;0.0001) than in non-expanding (p=0.034) cytotoxic T cells. Elevated CD112R expression level in CD8+ T cells were linked to a low tumor grade (p=0.048), absence of nodal metastasis (p=0.023) and a prolonged overall survival (p=0.041) but these associations were not retained in subgroups of either expanding or non-expanding CD8+ cells. Patients with an elevated fraction of CD8+ki67+CD112R+PD-1+cells exhibited a particularly good prognosis. In conclusion, our data reveal that “exhausted” CD112R+/ PD-1+CD8+ cytotoxic T lymphocytes are able to expand (ki67+). This observation in combination with the good prognosis of cancers with high number of expanding exhausted cells argues for retained cytotoxic activity of CD112R+/ PD-1+ CD8+ T lymphocytes.
Citation Format: Ronald Simon, Niclas Christian Blessin, Tim Mandelkow, Elena Bady, Claudia Hube-Magg, Guido Sauter, Maximilian Lennartz, Christoph Fraune, Sören A. Weidemann, Katharina Möller, Franziska Büscheck. Prognostic role of CD112R, PD-1 and Ki67 expression in CD8+cytotoxic T cells in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4970.
Abstract 4976: Combining measures of immune infiltration uncovers predictors of survival in high-grade serous ovarian cancer
Authors: Montfort Anne , Owen Steph J. , Piskorz Anna M. , Supernat Anna , Moore Luiza , Al-Khalidi Sarwah , Boehm Steffen , Pharoah Paul , McDermott Jacqueline , Balkwill Frances R. , Brenton James D. 
Published: September 2020

Abstract
Background: In colorectal and breast cancer, the density and localization of immune infiltrates provides strong prognostic information. We asked whether similar automated quantitation and combined analysis of immune infiltrates could refine prognostic information in high-grade serous ovarian carcinoma (HGSOC) and tested associations between patterns of immune response and genomic driver alterations.
Methods and Findings: Epithelium and stroma were semi-automatically segmented and the infiltration of CD45RO+, CD8+ and CD68+ cells was automatically quantified from images of 332 HGSOC patient tissue microarray cores. Epithelial CD8 (p=0.027, HR=0.83), stromal CD68 (p=3 × 10-4, HR=0.44) and stromal CD45RO (p=7 × 10-4, HR=0.76) were positively associated with survival and remained so when averaged across the tumor and stromal compartments.Using principal component analysis (PCA), we identified optimized multiparameter survival models that combined information from all immune markers (p=0.016, HR=0.88). There was no significant association between PTEN expression, type of TP53 mutation or presence of BRCA1/BRCA2 mutations and immune infiltrate densities or principal components.
Conclusions: Combining measures of immune infiltration provided improved survival modeling and evidence for the multiple effects of different immune factors on survival. The presence of stromal CD68+ and CD45RO+ populations was strongly associated with survival, underscoring the benefits that evaluating stromal immune populations may bring for prognostic immunoscores in HGSOC.
Citation Format: Anne Montfort, Steph J. Owen, Anna M. Piskorz, Anna Supernat, Luiza Moore, Sarwah Al-Khalidi, Steffen Boehm, Paul Pharoah, Jacqueline McDermott, Frances R. Balkwill, James D. Brenton. Combining measures of immune infiltration uncovers predictors of survival in high-grade serous ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4976.