tbuckley/cabot-search huggingface dataset:
Abstract 2158: Arsenic hexoxide has differential effects on cell proliferation and genome-wide gene expression in human primary mammary epithelial and mcf7 cells
Authors: Heeyoun Bunch, Donguk Kim, Na Yeon Park, Jaehyeon Jeong, Keunsoo Kang, Stuart K. Calderwood, Dong-Hyung Cho, Ill Ju Bae
Journal: Cancer Research (2021)

Abstract Arsenic is reportedly a biphasic inorganic compound for its toxicity and anticancer effects in humans. Recent studies have shown that certain arsenic compounds including arsenic hexoxide (AS4O6; hereafter, AS6) induce programmed cell death and cell cycle arrest in human cancer cells and murine cancer models. However, the mechanisms by which AS6 suppresses cancer cells are incompletely understood. In this study, we report the mechanisms of AS6 through transcriptome analyses. In particular, the cytotoxicity and global gene expression regulation by AS6 were compared in human normal and cancer breast epithelial cells. Using RNA-sequencing and bioinformatics analyses, differentially expressed genes in significantly affected biological pathways in these cell types were validated by real-time quantitative polymerase chain reaction and immunoblotting assays. Our data show markedly differential effects of AS6 on cytotoxicity and gene expression in human mammary epithelial normal cells (HUMEC) and Michigan Cancer Foundation 7 (MCF7), a human mammary epithelial cancer cell line. AS6 selectively arrests cell growth and induces cell death in MCF7 cells without affecting the growth of HUMEC in a dose-dependent manner. AS6 alters the transcription of a large number of genes in MCF7 cells, but much fewer genes in HUMEC. Importantly, we found that the cell proliferation, cell cycle, and DNA repair pathways are significantly suppressed whereas cellular stress response and apoptotic pathways increase in AS6-treated MCF7 cells. Together, we provide the first evidence of differential effects of AS6 on normal and cancerous breast epithelial cells, suggesting that AS6 at moderate concentrations induces cell cycle arrest and apoptosis through modulating genome-wide gene expression, leading to compromised DNA repair and increased genome instability selectively in human breast cancer cells. Citation Format: Heeyoun Bunch, Donguk Kim, Na Yeon Park, Jaehyeon Jeong, Keunsoo Kang, Stuart K. Calderwood, Dong-Hyung Cho, Ill Ju Bae. Arsenic hexoxide has differential effects on cell proliferation and genome-wide gene expression in human primary mammary epithelial and mcf7 cells [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 2158.
Abstract 1166: Structurally defined glycosaminoglycan mimetics exhibit preference for proteins of the growth factor family
Authors: Connor P. O'Hara, Nehru V. Sankaranarayanan, Rio S. Boothello, Bhaumik B. Patel, Umesh R. Desai
Journal: Cancer Research (2021)

Abstract Heparan sulfate (HS), a glycosaminoglycans of considerable structural diversity, has been implicated in a wide-variety of complex roles including regulation of cell signaling. Unfortunately, homogeneous HS is a dream that will likely be unfulfilled this century. To combat this, our lab has synthesized an array of non-saccharide glycosaminoglycan mimetics (NSGMs) that act as structural and functional mimetics of HS. A key advantage of our NSGMs is homogeneity, which enables assessing selectivity for recognition of target proteins with a high degree of confidence. A second advantage is the quantitative measurement of the affinity of these interactions, which affords a detailed understanding of the forces governing recognition of different proteins. Previously, we have shown a lead NSGM named G2.2 as a potent and selective inhibitor of colorectal cancer stem cells (CSCs) through phenotypic in-vitro and in-vivo assays. To improve upon the drug-like properties of G2.2, cholesterol-modified analogs (G2C, G5C, G8C) were designed to enhance potency and selectivity for protein target(s). Although the hypothesis is that G2.2 and its lipidic analogs target a ligand and/or a receptor belonging to CSC-relevant growth factors, the preferred target, if any, remains to be identified. More importantly, the relative order of preference in-vitro and its use in predicted in-vivo activity remains to be determined. In this work, we have performed a comprehensive biophysical screening of a panel of potential growth factor targets using biophysical methods to determine binding affinities, followed by quantitative measurement of the relative forces of interactions involved in target recognition. Our studies are complemented by computational experiments that provide a foundation for thermodynamic studies. Analysis of our results indicate that these NSGMs preferentially recognize certain growth factor proteins, suggesting that appropriately designed HS mimetics can be tailored to modulate a particular tyrosine kinase receptor pathway. More importantly, our results convey the principle that despite the presence of multiple sulfate groups, HS mimetics can be designed to exhibit selectivity for certain growth factor proteins. In fact, the sulfate groups on our molecules may actually contribute to the selectivity and potency of recognition, two central principles for the development of drugs. Citation Format: Connor P. O'Hara, Nehru V. Sankaranarayanan, Rio S. Boothello, Bhaumik B. Patel, Umesh R. Desai. Structurally defined glycosaminoglycan mimetics exhibit preference for proteins of the growth factor family [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 1166.
Keeping an eye on eye care: monitoring progress towards effective coverage
Authors: Stuart Keel, Andreas Müller, Sandra Block, Rupert Bourne, Matthew J Burton, Somnath Chatterji, Mingguang He, Van C Lansingh, Wanjiku Mathenge, Silvio Mariotti, Debbie Muirhead, M Mansur Rabiu, Thulasiraj D Ravilla, Serge Resnikoff, Juan Carlos Silva, Ian Tapply, Theo Vos, Ningli Wang, Alarcos Cieza
Journal: The Lancet Global Health (2021)

The eye care sector is well positioned to contribute to the advancement of universal health coverage within countries. Given the large unmet need for care associated with cataract and refractive error, coupled with the fact that highly cost-effective interventions exist, we propose that effective cataract surgery coverage (eCSC) and effective refractive error coverage (eREC) serve as ideal indicators to track progress in the uptake and quality of eye care services at the global level, and to monitor progress towards universal health coverage in general. Global targets for 2030 for these two indicators were endorsed by WHO Member States at the 74th World Health Assembly in May, 2021. To develop consensus on the data requirements and methods of calculating eCSC and eREC, WHO convened a series of expert consultations to make recommendations for standardising the definitions and measurement approaches for eCSC and eREC and to identify areas in which future work is required.
Abstract 1729: Reproducible, MoA-reflecting reporter-based bioassays to enable drug development of biosimilars and biobetters
Authors: Rich Moravec, Dun Li, Jennifer Wilkinson, Brad Swanson, Frank Fan, Mei Cong
Journal: Cancer Research (2021)

Abstract Cytokines and growth factors can be described as small immunomodulatory proteins secreted by a wide variety of cells including fibroblasts, endothelial and stromal cells, whose role it is to regulate surrounding cells in an autocrine, paracrine, or endocrine fashion. Immunocytokines represent a promising class of activators of the immune system, with the potential to be used alone or in combination with other therapeutic modalities. Many are currently FDA approved therapy agents (e.g. IFN, IL-2 and Epo), while others are targets for approved biological blocking therapies to support treatment of a variety of diseases. Examples of cytokine blocking agents include basiliximab (IL-2R), tocilizumab and sarilumab (IL-6R), siltuximab (IL-6), ustekinumab and its biosimilars (IL-12/IL-23 p40), secukinumab (IL-17A), bevasizumab (VEGF), and denosumab (RANKL). Many more are in development and trials as biosimilars and biobetters. IL-2 and IL-15 are still clinically important cytokines as researchers look to improve potency, patient tolerance and response by developing new molecules with sustained and targeted activities. We have developed luciferase reporter bioassays which individually can be used for the quantitation of a variety of cytokines and growth factors including IL-2, IL-6, IL-12, IL-15, IL-17, IL-23, TGF-β, VEGF and RANKL using respective mechanism of action pathways. The bioassay format is based on thaw-and use cells, eliminating the need to establish and pre-culture cytokine responsive cell lines which provides the benefits of convenience, reproducibility, and transferability. We demonstrate these assays measure cytokine response and inhibition with blocking drugs or potency changes from stressed samples. In summary, these reporter-based bioassays provide valuable tools for the development, stability testing, and potency determination in the manufacture of cytokine biosimilars and biobetters. Citation Format: Rich Moravec, Dun Li, Jennifer Wilkinson, Brad Swanson, Frank Fan, Mei Cong. Reproducible, MoA-reflecting reporter-based bioassays to enable drug development of biosimilars and biobetters [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 1729.
Abstract 18406: Insulin-Like Growth Factor-1 Increases Synthesis of Mature Type 1 Collagen via Induction of LARP6 Expression and Binding to the 5’ Stem-Loop Structure of Collagen mRNA
Authors: Christopher Blackstock, Yusuke Higashi, Sergiy Sukhanov, Patrice Delafontaine
Journal: Circulation (2013)

Structural integrity of the fibrous cap of atherosclerotic lesions is a major determinant of plaque stability. We have previously shown that either insulin-like growth factor-1 (IGF-1) -infusion or smooth muscle cell-specific IGF-1-overexpression increases collagen content in atherosclerotic plaque in apoe-/- mice. To identify the mechanism responsible for this increase in collagen, we investigated the effect of IGF-1 on the mRNA-binding protein, la-related protein 6 (LARP6). LARP6 has been shown to bind a conserved stem-loop secondary structure present in the 5’UTR of Col1a1 and Col1a2 mRNAs and to coordinate their efficient translation into the heterotrimer of type 1 collagen. Western blot from primary culture of human aortic smooth muscle cells (hASMCs) or mouse embryonic fibroblasts (mEFs) shows that IGF-1 increased expression of both LARP6 (~2.9-fold, p&lt;0.001) and procollagen-1α (~2.4-fold, p&lt;0.001) within 3 hours. Immunoprecipitation of LARP6, followed by measurement of Col1a1 and Col1a2 mRNA via qPCR indicates that IGF-1 increased association of LARP6 with Col1a1 and Col1a2 mRNA (p&gt;0.01). Mutation of the 5’stem-loop structure of Col1a1 mRNA (SL-/-), which inhibits binding of LARP6 but does not affect the coding region of the Col1a1 gene, abolished the ability of IGF-1 to increase collagen-1α (p&lt;0.001). Moreover, the SL-/- mutation blocked the ability of IGF-1 to increase the rate of pepsin-resistant collagen synthesis, measured via 3 H-proline incorporation assay (p&lt;0.001). Furthermore, western blot of crude aortic lysate from apoe-/- mice suggests that IGF-1-infusion increases LARP6 expression in VSMCs in vivo . To assess collagen maturation in vivo , aortic valve cross-sections were stained with picro-sirius red and examined using a polarizing microscope. Apoe-/- mice with smooth muscle cell-specific IGF-1-overexpression showed a strikingly amplified ratio of thick mature collagen fibers to thin immature collagen fibers in plaque. In summary, we show that IGF-1 increases expression of LARP6 in vascular smooth muscle cells leading to increased binding of LARP6 to Col1a1 and Col1a2 mRNAs and enhanced synthesis of mature type 1 collagen. These findings uncover a critical cellular mechanism whereby IGF-1 promotes plaque stability.
Severely low testosterone in men with COVID-19: A case-control study
Authors: P. Capogrosso, M. Pontillo, S. Gregori, M. Tassara, L. Boeri, C. Carenzi, C. Abbate, D. Cignoli, A.M. Ferrara, W. Cazzaniga, G. Landoni, P. Rovere Querini, F. Ciceri, F. Montorsi, A. Salonia
Journal: European Urology (2021)
Abstract 67: Paralleled convergence of antigen load, disease progression and systemic T cell exhaustion in lung cancer and HIV-1 infection
Authors: James L. Reading, Rachel Rosenthal, Lucas Black, Seng Kuong Ung, Claire Streatfield, Dominic Wooding, Joakim Esbjornsson, Eric Hunter, Sergio A. Quezada, Jonathan Hare, Charles Swanton
Journal: Cancer Research (2021)

Abstract Fatal immune failure in untreated HIV-1 infection is co-defined by evolution of viral escape mutants, increasing antigen diversity and concomitant T cell exhaustion. We have recently described mutational heterogeneity as a negative prognostic factor in primary non-small cell lung cancer (NSCLC), highlighted pathways of neoantigen-driven immune escape and reported a program of TMB-associated T cell exhaustion. Here we present interim analysis from a direct comparison of antigen evolution, peripheral T cell exhaustion and disease progression in 279 longitudinal samples from 64 HIV-1 infected volunteers in the retrospective IAVI protocol C cohort and 85 longitudinal samples from 35 NSCLC patients in the TRACERx study. Systemic PD1hi TOX+TCF7- Tex cell subsets were associated with virus load and CD4 loss in HIV-1 infection and tumour burden and disease progression in NSCLC. Levels of systemic Tex cells in NSCLC tracked with the extent of compartment-wide intra-tumoral CD4 and CD8 T cell dysfunction. Tex populations contracted upon antigen loss via ART in HIV-1, a process paralleled during surgical resection in NSCLC. Resurrection of systemic Tex populations was observed at disease recurrence in NSCLC, mediated in-part by post-operative persistence and re-expansion of minor circulating Tex subsets. These data highlight a common convergence of T cell exhaustion, antigen load and disease progression in distinct clinical conditions of impaired immune surveillance and chronic antigen stimulation. Citation Format: James L. Reading, Rachel Rosenthal, Lucas Black, Seng Kuong Ung, Claire Streatfield, Dominic Wooding, Joakim Esbjornsson, Eric Hunter, Sergio A. Quezada, Jonathan Hare, Charles Swanton. Paralleled convergence of antigen load, disease progression and systemic T cell exhaustion in lung cancer and HIV-1 infection [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 67.
Abstract 766: Expression of <i>HER-2</i> statue and PD-L1 is associated with prognosis in gastric cancer
Authors: Huifang Lv, Keran Sun, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Saiqi Wang, Yingjun Liu, Junling Zhang, Shiqing Chen, Xiaobing Chen
Journal: Cancer Research (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&amp;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 2228: Usage of ctDNA analysis to identify alterations with strong evidence for response or resistance to targeted therapy in patients with NENs
Authors: Kunli Du, Xueke She, Depei Huang, Xudong Shen, Hushan Zhang, Jianyong Zheng
Journal: Cancer Research (2021)

Abstract Background: Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. For nonresectable advanced NENs, the main treatment approaches including somatostatin analog, multiple TKIs, mTOR inhibitors and peptide receptor radionuclide therapy, whereas platinum-based chemotherapy is the main treatment for advanced high-grade and poorly differentiated NECs. Currently, there is no standard second-line treatment for NECs when disease progression. ctDNA as a non-invasive diagnostic avenue, which might potentially provide treatment guidance in NENs. Methods: We queried consecutive data from 40 NENs patients who underwent a targeted next-generation sequencing (NGS) assay performed by 3DMed Clinical Laboratory Inc., a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory of 3D Medicines Inc. between January, 2017 and June, 2020 in China, to identify the alterations detected in ctDNA. The alterations were classified based on the ranking in the OncoKB database as of January 2020. Results: In total, 40 of NENs patients detected with at least one alteration in ctDNA. The median age was 54 years, including 28 males and 12 females. Overall, 40.0% of patients had a Level 1 alteration, 22.5% of patients had a Level 2 alteration, and 22.5% of patients had a R1 alteration (selected alterations were outlined in Table). Conclusion: ctDNA analysis could provide information of alterations with strong evidence for targeted therapy or drug resistance based on the OncoKB database classification for NENs. Though the alterations are associated with other specific cancer types, the alterations still illustrate a part of NENs patients might have chance to be benefited from targeted therapy. AlterationsNumber of patients (%)Total Level 1 Alterations16 (40.0%)PIK3CA7 (17.5%)BRAF V600E2 (5.0%)BRCA22 (5.0%)MSI-H1 (2.5%)Total Level 2 Alterations9 (22.5%)ERBB2 activating4 (10.0%)MET amplication1 (2.5%)Total Level R1 alterations9 (22.5%)KRAS mut9 (22.5%) Citation Format: Kunli Du, Xueke She, Depei Huang, Xudong Shen, Hushan Zhang, Jianyong Zheng. Usage of ctDNA analysis to identify alterations with strong evidence for response or resistance to targeted therapy in patients with NENs [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 2228.
An Injectable Multifunctional Dual‐Phase Bead‐Reinforced Gelatin Matrix Permissive of Mesenchymal Stem Cell Infiltration for Musculoskeletal Soft Tissue Repair
Authors: Dajiang Du, Zhen Liu, Wanting Niu, Ding Weng, Teck Chuan Lim, Motoichi Kurisawa, Myron Spector
Journal: Advanced Healthcare Materials (2021)

Abstract This study develops a novel strategy for regenerative therapy of musculoskeletal soft tissue defects using a dual‐phase multifunctional injectable gelatin‐hydroxyphenyl propionic acid (Gtn‐HPA) composite. The dual‐phase gel consists of stiff, degradation‐resistant, ≈2‐mm diameter spherical beads made from 8 wt% Gtn‐HPA in a 2 wt% Gtn‐HPA matrix. The results of a 3D migration assay show that both the cell number and migration distance in the dual‐phase gel system are comparable with the 2 wt% mono‐phase Gtn‐HPA, but notably significantly higher than for 8 wt% mono‐phase Gtn‐HPA (into which few cells migrated). The results also show that the dual phase gel system has degradation resistance and a prolonged growth factor release profile comparable with 8 wt% mono‐phase Gtn‐HPA. In addition, the compressive modulus of the 2 wt% dual‐phase gel system incorporating the 8 wt% bead phase is nearly four‐fold higher than the 2 wt% mono‐phase gel (5.3 ± 0.4 kPa versus 1.5 ± 0.06 kPa). This novel injectable dual‐phase Gtn‐HPA composite thus combines the advantages of low‐concentration Gtn‐HPA (cell migration) with high‐concentration Gtn‐HPA (stiffness, degradation resistance, slower chemical release kinetics) to facilitate effective reparative/regenerative processes in musculoskeletal soft tissue.
Additional Counseling Support for Mothers With Gestational Hypertensive Disorders Regarding Neurodevelopmental Outcomes in Their Children
Authors: Stefania Triunfo
Journal: JAMA Pediatrics (2021)

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NT-proBNP for Risk Prediction in Heart Failure
Authors: Giuseppe Vergaro, Francesco Gentile, Laura M.G. Meems, Alberto Aimo, James L. Januzzi, A. Mark Richards, Carolyn S.P. Lam, Roberto Latini, Lidia Staszewsky, Inder S. Anand, Jay N. Cohn, Thor Ueland, Lars Gullestad, Pål Aukrust, Hans-Peter Brunner-La Rocca, Antoni Bayes-Genis, Josep Lupón, Akiomi Yoshihisa, Yasuchika Takeishi, Michael Egstrup, Ida Gustafsson, Hanna K. Gaggin, Kai M. Eggers, Kurt Huber, Greg D. Gamble, Lieng H. Ling, Kui Tong Gerard Leong, Poh Shuah Daniel Yeo, Hean Yee Ong, Fazlur Jaufeerally, Tze P. Ng, Richard Troughton, Robert N. Doughty, Gerry Devlin, Mayanna Lund, Alberto Giannoni, Claudio Passino, Rudolf A. de Boer, Michele Emdin
Journal: JACC Heart Failure (2021)