bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 713: Inhibition of pseudo SARS-CoV-2 binding activity of a anti-cancer polypharmacological agent analogs
Authors: Papineni Rao V. , Adhikary Amitava , Tandon Ritesh , Mitra Dipanwita 
Published: July 2021

Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a single-stranded RNA virus with largest genomes (∼ 29,800 bases) of all viruses, causes the infectious disease, COVID-19. SARS-CoV-2 is a zoonotic betacoronavirus transmitted through airborne and fecal-oral routes infecting nasal, lung, and intestinal tissues causing over 26 million confirmed coronavirus disease 2019 (COVID-19) cases and nearly 900,000 associated deaths worldwide as of September 2020. The surface of SARS-CoV-2 is covered with copies of spike glycoprotein (SGP) that plays a pivotal role in virus entry in host cells utilizing angiotensin-converting enzyme 2 (ACE2) as an attachment and entry receptor. We have successfully made a high titer replication-incompetent third-generation lentiviral vector pseudotyped with SARS-2-CoV SGP (pLV-S). Upon successful attachment and entry, the lentiviral vector causes enhanced green fluorescent protein (eGFP) to be expressed in the infected cell. Here, we show how the polypharmacological agent, 2-Deoxy-D-glucose (2-DG), a glucose mimic, and well characterized anti-cancer drug, and its analogs inhibit spike protein binding to the ACE2 receptors. This is as suggested from the 2DG and two analogs inhibition, with a low micromolar affinity, the pLV-S attachment and entry resulting in reduced cell fluorescence of infected HEK293 cells. In addition, we describe 2DG and analogs has the potential to deliver polypharmacological effects on the COVID-through inhibition of glycolysis (at energy status), modulation of inflammatory responses (cytokine storm) and alterations in glycosylation of viral proteins. A unique class of adjuvants and mitigants in the anti-SARS-CoV-2 activity is presented here.
Citation Format: Rao V. Papineni, Amitava Adhikary, Ritesh Tandon, Dipanwita Mitra. Inhibition of pseudo SARS-CoV-2 binding activity of a anti-cancer polypharmacological agent analogs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 713.
Abstract 739: Preclinical and clinical activity of SAR439859, Amcenestrant, a next generation SERD
Authors: Shomali Maysoun , Sun Fangxian , Besret Laurent , Caron Anne , Lee Joon Sang , El-Ahmed Youssef , Schio Laurent , Pollard Jack , Pelekanou Vasiliki , Cohen Patrick , Celanovic Marina , Herold Christina , Soria Chris , Debussche Laurent , Bouaboula Monsif 
Published: July 2021

Abstract
Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. Selective estrogen receptor degraders (SERDs), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Here we describe the discovery of SAR439859 (Amcenestrant), a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models including MCF7-ESR1 mutant-Y537S mouse tumors and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. Importantly, in these mutant ESR1 models, we demonstrate that the efficacy of SAR439859 was increased when coadministered with palbociclib, an inhibitor of cyclin-dependent kinase 4 and 6. In the clinical setting, SAR439859 also demonstrated a high level of target engagement, ER degradation and inhibition of ER signaling as well as encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER-positive breast cancer. These findings indicate that SAR439859 would provide therapeutic benefit to patients with ER+ breast cancer, including those who are resistant to endocrine therapy with both wild-type and mutant ER.
Citation Format: Maysoun Shomali, Fangxian Sun, Laurent Besret, Anne Caron, Joon Sang Lee, Youssef El-Ahmed, Laurent Schio, Jack Pollard, Vasiliki Pelekanou, Patrick Cohen, Marina Celanovic, Christina Herold, Chris Soria, Laurent Debussche, Monsif Bouaboula. Preclinical and clinical activity of SAR439859, Amcenestrant, a next generation SERD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 739.
Abstract 766: Expression of HER-2 statue and PD-L1 is associated with prognosis in gastric cancer
Authors: Lv Huifang , Sun Keran , Nie Caiyun , Chen Beibei , Wang Jianzheng , Xu Weifeng , Wang Saiqi , Liu Yingjun , Zhang Junling , Chen Shiqing , Chen Xiaobing 
Published: July 2021

Abstract
Background PD-L1 and HER-2 as routine biomarkers in gastric cancer (GC). However, little research has been done to investigate the correlation among PD-L1, HER-2, and clinical features in GC.
Methods Between Jan. 2013 and May 2020, a total of 120 GC patients treated with chemotherapy were admitted to Henan Tumor Hospital. We retrospectively identified PD-L1, HER-2 level before chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between PD-L1/HER-2 levels and progression-free survival (PFS).
Results We retrospectively analyzed 120 patients with gastric cancer, including 17 patients with HER-2 positive and 103 patients with HER-2 negative GC. The results showed that the expression of PD-L1 was closely correlated with HER-2 gene status, with statistical significance (P =0.015). Patients with PD-L1/HER-2 positive obtained lower PFS compared to PD-L1/HER-2 negative (mPFS: 6.4 vs. 11.1 months, P=0.014, mPFS: 5.3 vs. 11.1 months, P=0.002). And the PD-L1 negative and HER-2 negative had the best PFS than other groups (P=0.0008). In a multivariate model, PD-L1 statue, HER-2 statue, tumor location and tumor differentiation remained independent prognostic indicators for PFS (P&lt;0.05).
Conclusion HER-2 status could predict the efficacy of immune checkpoint inhibitors, and HER-2 status combined with PD-L1 level could predict the prognosis of GC patients.
Citation Format: Huifang Lv, Keran Sun, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Saiqi Wang, Yingjun Liu, Junling Zhang, Shiqing Chen, Xiaobing Chen. Expression of HER-2 statue and PD-L1 is associated with prognosis in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 766.
Abstract 77: MSC loaded oncolytic virus and expressing immunomodulators have therapeutic efficacy in advanced melanomas
Authors: Kanaya Nobuhiko , Vazquez Maria Lopez , Torres Arnaldo J. Franco , Kitamura Yohei , Boland Genevieve M. , Shah Khalid 
Published: July 2021

Abstract
Patients with advanced melanoma have a high propensity to metastasize to the brain and numerous investigational treatments with targeted agents have shown modest response in melanoma brain metastatic patients. Therefore, there is an urgent need to develop innovative therapies for such tumors. Oncolytic herpes simplex virus (oHSV) that selectively replicate in tumor cells and illicit an antitumor effect via oncolysis and production of neoantigens is among the recently approved promising therapies for primary melanoma patients. However, virus neutralization, and inefficient extravasation are the major barriers to the effective systemic delivery of oHSV to target metastatic tumor lesions in the brain. We have previously shown that mesenchymal stem cells (MSC) armed with different oHSV variants (MSC-oHSV) home to metastatic tumor lesions and have therapeutic benefits in melanoma brain metastases (MBM) models. To enhance therapeutic efficacy for metastasis melanoma, we investigated the novel combined therapy using MSC loaded with oHSV and simultaneously MSC releasing GM-CSF. Based on our TCGA data indicating significant loss of PTEN expression in late-stage metastatic melanoma, we tested MSC based therapeutics in PTEN mutant mouse melanomas. We show that MSC loaded oHSV effectively kills PTEN mutant syngeneic tumor cells in vitro. Next, we established MSC secreting GM-CSF and tested the abscopal effects as well as the antitumor efficacy in combination with MSC-oHSV in PTEN mutant syngeneic bilateral subcutaneous tumor model. The combined MSC based therapy showed significant therapeutic effects at both the treated and untreated site compared to control therapies. Interestingly, when these mice after combination therapy were re-challenged with mouse melanoma cells injected into brain, all mice remained tumor free. The combined MSC therapy induced effector memory CD8 and central memory CD8 cells in spleen and there was no toxicity in major organs post-therapy. In conclusion, our data indicate that combined MSC-oHSV/GM-CSF therapy is a promising novel therapy for advanced melanomas.
Citation Format: Nobuhiko Kanaya, Maria Lopez Vazquez, Arnaldo J. Franco Torres, Yohei Kitamura, Genevieve M. Boland, Khalid Shah. MSC loaded oncolytic virus and expressing immunomodulators have therapeutic efficacy in advanced melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 77.
Abstract 771: Cytokine expression and levels in plasma-derived exosomes are underestimated as contributors to cytokine profiles in cancer patients and healthy donors
Authors: Hong Chang- Sook , Diergaarde Brenda , Whiteside Theresa L. 
Published: July 2021

Abstract
Exosomes play a key role in cell-to-cell signaling. Emerging evidence suggests that biologically active cytokines may be present on the surface or in the lumen of exosomes. We evaluated cytokines in exosomes isolated by size-exclusion chromatography from pre-cleared plasma of 13 patients with head and neck cancer and three healthy donors (HDs). Paired untreated plasma and detergent-treated exosomes were studied by Luminex and cytokine microarrays. On-bead flow cytometry was used to assess relative levels of cytokines on the surface or in the vesicle lumen. Measured by Luminex, for the majority of cytokines (10 of 12), the level observed in plasma was concordant with the level in exosomes. MCP-1 and MIF were the exceptions. They were highly elevated in untreated plasma. Cytokine levels in exosomes determined in parallel by Luminex and the microarray were concordant, except for IL-1β and GM-CSF, which were elevated in Luminex assays. Our data show that only a fraction of most cytokines in untreated plasma is soluble and detectable by Luminex, while the rest is associated with exosomes and can only be detected after exosome permeabilization. Exosome cytokine profiles and levels measured by either method discriminated cancer patients from healthy donors as did levels of soluble cytokines in plasma. By on bead flow cytometry, the relative levels of cytokines in the lumen and on the exosome surface were confirmed for IFN-γ, IL-17, TNF-α and TGF-β, while IL-8 was only detected in the exosome lumen. Thus, cytokines are packaged into exosomes, which carry cytokines on the surface and in the vesicle lumen and contribute to inaccurate, largely underestimated, levels of plasma cytokines reported by laboratories.
Citation Format: Chang- Sook Hong, Brenda Diergaarde, Theresa L. Whiteside. Cytokine expression and levels in plasma-derived exosomes are underestimated as contributors to cytokine profiles in cancer patients and healthy donors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 771.
Abstract 778: CD24 mutant p53 contribute to racial disparities in prostate cancer
Authors: Cui Xuelian , Wang Shuaibin , Wang Lizhong 
Published: July 2021

Abstract
African-American (AA) men have the highest rate of prostate cancer among racial or ethnic groups. CD24, a cell-surface protein anchored by glycosyl-phosphatidyl-inositol (GPI), often is over-expressed in cancers and serves as a marker for poor prognosis of human cancer, including prostate cancer. Using a functional analysis of prostate cancer cells, we found a CD24-dependent inactivation of mutant p53, but the clinical significance of this observation remained uncertain. Here, we validated these results with samples of human prostate cancer and explored the role of a CD24-p53 axis in racial disparities of prostate cancer. Our bioinformatics analysis of public datasets, including TCGA data, confirmed higher levels of CD24 mRNA expression in late-stage and metastatic prostate cancer. In the present study, we addressed the association of CD24 with mutant p53 and their differential expression between AA and European-American (EA) prostate cancers and assessed whether cells with CD24 and mutant p53 contribute to health disparities in prostate cancer. CD24, mutant p53, MDM2, and ARF proteins were expressed in 55%, 24%, 39%, and 68% of prostate cancer samples, respectively. CD24 and mutant p53 were present more frequently in late-stage and metastatic prostate cancer. The presence of CD24 was associated with a &gt; 4-fold risk of metastasis, which included lymph node and distant metastases. H-score analysis showed positive correlations of CD24 expression with mutant p53 and MDM2. A racial disparity was evident for CD24 but not for mutant p53. In 32 CD24+/mutant p53+ cases, a TP53R273H mutation was found in five cases, but no TP53R175H mutation was found. The CD24-p53 axis may contribute to aggressive and metastatic prostate cancers, especially those of AAs.
Citation Format: Xuelian Cui, Shuaibin Wang, Lizhong Wang. CD24 mutant p53 contribute to racial disparities in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 778.
Abstract 809: Neurotensin increases tyrosine phosphorylation of HER3
Authors: Moody Terry W. , Ramosalvarez Irene , Jensen Robert T. 
Published: July 2021

Abstract
Neurotensin (NTS) is an autocrine growth factor for non-small cell lung cancer cells. NTS stimulates and the NTSR1 antagonist SR48692 inhibits NSCLC growth (Moody et al., Life Sci 2014; 100: 25). NSCLC patients, whose tumors have high NTSR1, have significantly lower relapse-free survival than those with low NTSR1 (Younes et al., Oncotarget 2014; 5: 8252). NTS addition to NSCLC cells increases the tyrosine phosphorylation of the EGFR and HER2 (Moody et al., Eur J Pharmacol 2019; 865:172735). Activation of HER3 in NSCLC mediates aggressive growth and drug resistance. Therefore the ability of NTSR1 to regulate transactivation of HER3 was investigated. By RT-PCR, HER3 and NTSR1 but not NTSR2 mRNA was present in NSCLC cells. NTS addition to NCI-H358 or H441 cells increased HER3 and ERK tyrosine phosphorylation by 210% and 240%, respectively and the increase caused by NTS was antagonized by SR48692 or mAb3481 (HER3 mAb). The increase is phosphorylation of Tyr1289-HER3 caused by NTS or neuregulin-1 addition to NSCLC cells was due to the formation of HER2-HER3 and EGFR-HER3 heterodimers. NTSR1 regulation of HER3 or Akt phosphorylation was impaired by PP2 (Src inhibitor) or GM6001 (MMP inhibitor). Because N-acetylcysteine (antioxidant) or Tiron (superoxide scavenger) inhibited the ability of NTS to increase HER3 phosphorylation, reactive oxygen species (ROS) are essential. Using a clonogenic assay, NTS increased NSCLC colony number whereas SR48692 or mAb3481 reduced colony number. The results indicate that NTS increased HER3 tyrosine phosphorylation in a ROS-/Src-/MMP-dependent manner. In summary, NTSR1 transactivates HER3 resulting in ERK and Akt phosphorylation increasing the proliferation and survival of NSCLC cells.
Citation Format: Terry W. Moody, Irene Ramosalvarez, Robert T. Jensen. Neurotensin increases tyrosine phosphorylation of HER3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 809.
Abstract 825: Genetically determined elevated C-reactive protein levels and chronic inflammation status associated with primary colorectal cancer risk: Mendelian randomization with lifestyle interactions
Authors: Jung Su Yon , Yu Herbert , Pellegrini Matteo , Papp Jeanette C. , Sobel Eric M. , Zhang Zuo-Feng 
Published: July 2021

Abstract
Purpose: Immune-related etiologic pathways in the development of colorectal cancer (CRC) have not been convincingly determined and may be confounded by lifestyle factors or reverse causality. We investigated the genetically predicted C-reactive protein (CRP) phenotype in the potential causal pathway of primary CRC risk in postmenopausal women in a Mendelian randomization (MR) framework.
Methods: We employed individual-level data of the Women's Health Initiative Database for Genotypes and Phenotypes Study, which consists of 5 genome-wide association (GWA) studies, including 10,142 women, 737 of whom developed primary CRC. We examined 61 GWA single-nucleotide polymorphisms (SNPs) associated with CRP by using weighted/penalized MR weighted-medians and MR gene-environment interactions that allow some relaxation of the strict variable requirements and attenuate the heterogeneous estimates of outlying SNPs.
Results: In lifestyle-stratification analyses, genetically determined CRP exhibited its effects on the decreased CRC risk in non-viscerally obese and high-fat diet subgroups. In contrast, genetically driven CRP was associated with an increased risk for CRC in women who smoked 15 or more cigarettes/day, with significant interaction of the gene-smoking relationship. Further, a substantially increased risk of CRC induced by CRP was observed in relatively short-term users (less than 5 years) of estrogen (E)-only and also longer-term users (longer than 5 years) of E plus progestin.
Conclusions: Our findings may provide novel evidence on immune-related etiologic pathways connected to CRC risk and suggest the possible use of CRP as a CRC-predictive biomarker in women with particular behaviors and CRP marker-informed interventions to reduce CRC risk.
Citation Format: Su Yon Jung, Herbert Yu, Matteo Pellegrini, Jeanette C. Papp, Eric M. Sobel, Zuo-Feng Zhang. Genetically determined elevated C-reactive protein levels and chronic inflammation status associated with primary colorectal cancer risk: Mendelian randomization with lifestyle interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 825.
Abstract 829: Genetic risk factors for histiocytic sarcoma in a canine disease model
Authors: Evans Jacquelyn M. , Parker Heidi G. , Plassais Jocelyn , Rutteman Gerard R. , Ostrander Elaine A. 
Published: July 2021

Abstract
Histiocytic sarcoma is a rare, aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart in dogs affects two breeds at unusually high frequency, with 20-25% of Flatcoated Retrievers and Bernese Mountain Dogs developing histiocytic sarcoma, while the disease is extremely rare in other breeds. In this study, we leveraged the canine model system to investigate genetic risk factors for histiocytic sarcoma in the Flatcoated Retriever. Population bottlenecks and artificial selection during breed formation within last 200 years have created the unique breed structure in dogs, characterized by long linkage disequilibrium and low within-breed genetic diversity. This allows for the identification of disease-associated traits with relatively few markers and individuals. We conducted multiple genome-wide association studies in Flatcoated Retrievers in which we identified two loci conferring risk for histiocytic sarcoma (177 cases and 132 controls, total). The first locus, on canine chromosome (CFA) 5, also colocalizes with previously identified risk for hemangiosarcoma and B-cell lymphoma, two hematopoietic malignancies in the closely related golden retriever breed. The second locus is unique to the Flatcoated Retriever and increases risk for histiocytic sarcoma in combination with CFA5. There have been multiple reports of human histiocytic sarcoma diagnosis concurrent with other hematological cancers, including lymphoma, suggested to be the result of transdifferentiation or a common neoplastic progenitor. Here we link germline predisposition for histiocytic sarcoma and B-cell lymphoma to the same locus in retrievers. Subsequent whole genome, transcriptome, and ChIP sequencing, highlighted candidate genes at each locus with roles in cell migration, as well as candidate regulatory variants with predicted impact on transcription factor binding. This comprehensive, multi-omics approach has been previously largely unexplored in the canine model. Here we advance our knowledge of the biology of histiocytic sarcoma, which will have direct impact on canine health and elucidate the genetic mechanisms underlying a rare human cancer.
Citation Format: Jacquelyn M. Evans, Heidi G. Parker, Jocelyn Plassais, Gerard R. Rutteman, Elaine A. Ostrander. Genetic risk factors for histiocytic sarcoma in a canine disease model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 829.