bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO088: Sensitivity of cancer cells to oncolytic viruses is defined by IWS1 phosphorylation dependent epigenetic regulation of U2AF2 splicing and nucleocytoplasmic export of type I IFN transcripts
Authors: Laliotis Georgios I. , Kenney Adam D. , Chavdoula Evangelia , Orlacchio Arturo , Anastas Vollter , La Ferlita Alessandro , Kaba Abdul , Sehgal Lalit , Coppola Vincenzo , Yount Jacob S. , Tsichlis Philip N. 
Published: February 2021

Abstract
We have previously shown that loss of IWS1 phosphorylation promotes the alternative RNA splicing of U2 Associated-Factor 2 (U2AF2), resulting in transcripts lacking exon 2. This exon encodes part of the Serine-Rich (SR) domain of U2AF65, which is responsible for its binding with pre-mRNA Processing Factor 19 (Prp19). Here, we show that whereas both U2AF65 isoforms bind cytoplasmic accumulation response elements (CAR-E) of intronless mRNAs, the loading of Prp19 occurs only in exon 2-containing U2AF65, in cells expressing phosphorylated IWS1, promoting their nucleocytoplasmic export. Furthermore, this Prp19 loading is RNA Pol II dependent. Given that IFNA1 and IFNB1 are among the target genes, the expression of IFNα and IFNβ was decreased in cells deficient in IWS1 phosphorylation, and their sensitivity to the oncolytic VSV and Reovirus virus infection was increased accordingly. More importantly, treatment of the lung adenocarcinoma cells with the pan-AKT inhibitor, MK2206 phenocopied the loss of IWS1 phosphorylation and showed increased sensitivity to oncolytic viral infection. These data identify a novel mechanism by which the AKT/p-IWS1 axis, via the epigenetic regulation of alternative RNA splicing, contribute to the sensitivity to oncolytic viruses.
Citation Format: Georgios I. Laliotis, Adam D. Kenney, Evangelia Chavdoula, Arturo Orlacchio, Vollter Anastas, Alessandro La Ferlita, Abdul Kaba, Lalit Sehgal, Vincenzo Coppola, Jacob S. Yount, Philip N. Tsichlis. Sensitivity of cancer cells to oncolytic viruses is defined by IWS1 phosphorylation dependent epigenetic regulation of U2AF2 splicing and nucleocytoplasmic export of type I IFN transcripts [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO088.
Abstract PR005: Highly potent fully human anti-VISTA antibodies – A new target checkpoint inhibitor against immunosuppressive myeloid cells
Authors: Guillaudeux Thierry , Tarcha Eric , Bader Robert , Dutzar Benjamin , Eyde Nathan , Frazier Emily , Jurchen David , Lance Remington , Loomis Cristina , Lustig Kurt , Ovechkina Yulia , Peckham David , Posakony Jeff , Sridhar Shaarwari , Xu Mei , Iadonato Shawn 
Published: February 2021

Abstract
V-domain Immunoglobulin Suppressor of T cell Activation (VISTA/PD-1H) is a B7 family ligand expressed on circulating and intratumoural myeloid cells as well as Treg and NK cells. It has been shown to inhibit T cell responses in vitro and in preclinical models. In patients, VISTA is also a potential mediator of resistance to anti-CTLA-4 and anti-PD1 therapies and therefore is a valuable new target for cancer immunotherapy. Kineta has analyzed 107 fully human ScFv antibodies directed against VISTA. Our lead candidates exhibit high potencies in the subnanomolar range and are also characterized by a long kDis. They specifically target human and cynomolgus monkey VISTA on a singular unique epitope. In a Staphylococcus Enterotoxin B T-cell activation assay, Kineta’s anti-VISTA antibodies efficiently induce IFNg secretion. They also promote strong maturation of Antigen Presenting Cells with an increase of CD80 and HLA-DR surface expression as well as CXCL10 secretion. The mechanism of action is mediated in part by NK cells. We demonstrated that myeloid cells acquire a high level of VISTA expression during MDSC or M2 differentiation in vitro and that Kineta’s anti-VISTA antibodies prevent the differentiation of MDSC as well as their immunosuppressive activity against T cells. Anti-VISTA antibodies mediate single-agent antitumor effects in syngeneic tumor models in wild-type mice and show enhanced activity in combination with anti-PD1 and anti-CTLA-4 treatment. Candidate anti-VISTA antibodies have also been evaluated in exploratory tolerability and PK studies in cynomolgus monkey. These studies demonstrated that multiple weekly doses of antibodies are well-tolerated with appropriate PK for lead selection and optimization. Our results strongly favor further characterization and continued development of selected lead antibodies for the potential treatment of colder, less immunogenic tumors.
This abstract is also being presented as PO035.
Citation Format: Thierry Guillaudeux, Eric Tarcha, Robert Bader, Benjamin Dutzar, Nathan Eyde, Emily Frazier, David Jurchen, Remington Lance, Cristina Loomis, Kurt Lustig, Yulia Ovechkina, David Peckham, Jeff Posakony, Shaarwari Sridhar, Mei Xu, Shawn Iadonato. Highly potent fully human anti-VISTA antibodies – A new target checkpoint inhibitor against immunosuppressive myeloid cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR005.
Abstract PR009: The functional genomic landscape of recurrent glioblastoma
Authors: Chokshi Chirayu , Tieu David , Brown Kevin , Venugopal Chitra , Liu Lina , Kuhlman Laura , Chan Katherine , Tong Amy , Savage Neil , McKenna Dillon , Aghaei Nikoo , Subapanditha Minomi , Salamoun Joseph M , Rossotti Martin , Wipf Peter , Sharlow Elizabeth , Lazo John S. , Kislinger Thomas , Henry Kevin , Lu Yu , Moffat Jason , Singh Sheila K. 
Published: February 2021

Abstract
Glioblastoma (GBM) is a highly fatal brain cancer where mortality is predominantly caused by disease recurrence and lack of second-line therapies. Here, utilizing genome-wide CRISPR-Cas9 screening, we uncover treatment-based conditional genetic interactions modulating sensitivity to combined radiation therapy (RT) and temozolomide (TMZ), the standard of care treatment administered to over 70% of glioblastoma patients. To investigate therapy-induced changes in the functional landscape of glioblastoma stem cells (GSCs) without confounding patient-to-patient differences, we systematically mapped genetic dependencies in patient-matched pre-treatment primary and post-treatment recurrent GSCs. This comparison highlights a remodelling of genes and pathways regulating tumor cell survival at disease relapse, arming recurrent GSCs with newly acquired genetic drivers and further loss of tumor suppressors. Among these genes, we identify PTP4A2, encoding protein tyrosine phosphatase 4A2, as a major regulator of stemness and tumorigenicity in recurrent GSCs. Genetic perturbation or pharmacological inhibition of PTP4A2 influences the phosphorylation status and expression of interacting proteins belonging to axonal guidance pathways, as phosphoproteomic studies showed specific enrichment in axon guidance regulator Roundabout Guidance Receptor 1 (ROBO1) in recurrent GSCs. We therefore designed and developed efficacious Camelid biotinylated single-domain antibody (bio-sdAb) and tetrameric complexes targeting human ROBO1 (MKRo-20). Subsequently, we orthotopically engrafted recurrent GSCs into immunocompromised mice and administered local treatments of tetrameric MKRo-20. All mice treated with tetrameric MKRo-20 were rendered tumor free, suggesting that modulation of ROBO1 with bio-sdAbs presents a new immunotherapeutic strategy to target recurrent glioblastoma. Our work reveals a context-specific dependence on axonal guidance through a PTP4A2-ROBO axis in recurrent glioblastoma, highlighting new avenues of therapeutic intervention for second-line therapy in GBM.
This abstract is also being presented as PO025.
Citation Format: Chirayu Chokshi, David Tieu, Kevin Brown, Chitra Venugopal, Lina Liu, Laura Kuhlman, Katherine Chan, Amy Tong, Neil Savage, Dillon McKenna, Nikoo Aghaei, Minomi Subapanditha, Joseph M Salamoun, Martin Rossotti, Peter Wipf, Elizabeth Sharlow, John S. Lazo, Thomas Kislinger, Kevin Henry, Yu Lu, Jason Moffat, Sheila K. Singh. The functional genomic landscape of recurrent glioblastoma [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR009.
Abstract PR010: Potentiating the efficacy of immune checkpoint blockade by targeting the epithelial-to-mesenchymal transition (EMT) in breast carcinomas
Authors: Dongre Anushka , Rashidian Mohammad , Ng Eaton Elinor , Reinhardt Ferenc , Thiru Prat , Zagorulya Maria , Nepal Sunita , Banaz Tuba , Martner Anna , Spranger Stefani , Weinberg Robert A. 
Published: February 2021

Abstract
The epithelial-to-mesenchymal transition (EMT), which conveys epithelial (E) carcinoma cells to quasi-mesenchymal (qM) states, enables these cells to gain tumor-initiating stem like abilities, metastasize and acquire resistance to several drug and chemotherapeutic regimens. In addition to these aforementioned features, we have recently demonstrated that the EMT program also contributes to the generation of an immunosuppressive tumor microenvironment (TME) in breast carcinomas and confers resistance to immune checkpoint blockade therapies. Specifically, qM tumors recruit immunosuppressive cells to their TME and are refractory to checkpoint blockade, while E tumors recruit CD8+ T-cells instead and are sensitive to checkpoint blockade. Importantly, minority populations of qM cells within a tumor can cross-protect their more E neighbors from immune attack. The underlying mechanisms by which this immunosuppression and cross-protection are achieved have been unclear. Using a combination of novel E and qM tumor models arising in syngeneic immunocompetent hosts combined with CRISPR/Cas9 and transcriptomic approaches, we demonstrate that qM but not E tumors are specifically associated with an immunosuppressive gene signature. Furthermore, abrogation of carcinoma cell-derived factors (CD73, Csf1 or Spp1) specifically associated with the qM state, prevents the assembly of an immunosuppressive TME and sensitizes otherwise refractory qM tumors partially or completely to checkpoint blockade immunotherapy. Taken together, our work indicates that carcinoma cell-intrinsic factors specifically associated with residence in the qM state can directly influence their response to anti-tumor immunity and checkpoint blockade. As a result, this work brings to the forefront the possibility of using the epithelial-mesenchymal state of carcinoma cells as an important surrogate marker that can be used to predict responses to immune checkpoint blockade therapies.
This abstract is also being presented as PO038.
Citation Format: Anushka Dongre, Mohammad Rashidian, Elinor Ng Eaton, Ferenc Reinhardt, Prat Thiru, Maria Zagorulya, Sunita Nepal, Tuba Banaz, Anna Martner, Stefani Spranger, Robert A. Weinberg. Potentiating the efficacy of immune checkpoint blockade by targeting the epithelial-to-mesenchymal transition (EMT) in breast carcinomas [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR010.
Abstract PR011: Selective inhibition of VEGF binding to VEGFR2 promotes an immune stimulatory microenvironment in murine models of breast cancer
Authors: Zhang Yuqing , Huang Huocong , Sorrelle Noah , Brekken Rolf 
Published: February 2021

Abstract
Vascular endothelial growth factor-A (VEGF) is the dominant angiogenic factor that promotes tumor neovascularization, making it a critical target for cancer therapy. VEGF binds and activates VEGF receptor 1 (VEGFR1) and VEGFR2, with VEGFR2 being the principal receptor mediating VEGF-induced angiogenesis while VEGFR1 has a negative regulatory effect on this process. Previously, we found that selective inhibition of VEGF binding to VEGFR2 with a fully human monoclonal antibody (r84) or its mouse chimeric counterpart (mcr84) is sufficient for effective control of tumor growth in preclinical models of breast cancer. However, accumulating evidence indicates that the effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. Concordantly, we have shown that VEGF blockade regulates immune cell trafficking across the endothelium by increasing the expression of adhesion molecules while decreasing FasL expression on tumor vasculature. In addition, specifically blocking VEGF binding to VEGFR2 promotes an immune stimulatory microenvironment by enhancing activation of CD8+ cytotoxic T cells as evidenced by elevated secretion of Granzyme B and IFN-γ. In addition, VEGF blockade also reduces FoxP3+ regulatory T cell infiltration in multiple murine models of cancer. We and others have shown that immune cells express receptors for VEGF. Our data indicate that VEGFR2 expression is elevated on myeloid cells selectively in tumor-bearing animals. Consistent with VEGFR2 expression, treatment with mcr84 results in a reduction in macrophage/myeloid cell infiltration into murine breast tumors. In conclusion, our results enhance understanding of the function of VEGFR2 signaling on myeloid cells and suggest that selective inhibition of VEGF from binding VEGFR2 facilitates immune activation landscape in breast cancer models, which might enhance the efficacy of immune checkpoint blockade.
This abstract is also being presented as PO045.
Citation Format: Yuqing Zhang, Huocong Huang, Noah Sorrelle, Rolf Brekken. Selective inhibition of VEGF binding to VEGFR2 promotes an immune stimulatory microenvironment in murine models of breast cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR011.
Effect of Inotropes on Patient-Reported Health Status in End-Stage Heart Failure
Authors: Clarke John-Ross D. , Riello Ralph , Allen Larry A. , Psotka Mitchell A. , Teerlink John R. , Lindenfeld JoAnn , Desai Nihar R. , Ahmad Tariq 
Published: February 2021

Background:
A growing population of patients with end-stage heart failure (HF) with reduced ejection fraction has limited treatment options to improve their quality and quantity of life. Although positive inotropes have failed to show survival benefit, these agents may enhance patient-reported health status, that is, symptoms, functional status, and health-related quality of life. We sought to review the available clinical trial data on positive inotrope use in patients with end-stage HF and to summarize evidence supporting the use of these agents to improve health status of patients with end-stage HF.

Methods:

A literature review of randomized controlled trials examining the use of positive inotropy in HF with reduced ejection fraction was conducted. We searched MEDLINE, SCOPUS, and Web of Science between January 1980 to December 2018 for randomized controlled trials that used as their main outcome measures the effects of inotrope therapy on (1) morbidity/mortality, (2) symptoms, (3) functional status, or (4) health-related quality of life. Inotropes of interest included adrenergic agents, phosphodiesterase inhibitors, calcium sensitizers, myosin activators, and SERCA2a (sarcoplasmic reticulum Ca
2+
-ATPase) modulators.

Results:
Twenty-two out of 26 inotrope randomized controlled trials measured the effect of inotropes on at least one patient-reported health status domain. Among the 22 studies with patient-related health status outcomes, 11 (50%) gauged symptom response, 15 (68%) reported functional capacity changes, and 12 (54%) reported health-related quality of life measures. Fourteen (64%) of these trials noted positive outcomes in at least one health status domain measured; 11 (79%) of these positive studies used agents that worked through phosphodiesterase inhibition.

Conclusions:
There has been a lack of standardization surrounding measurement of patient-centered outcomes in studies of inotropes for end-stage HF with reduced ejection fraction. The degree to which positive inotropes can improve patient-reported health status and the adverse risk they pose remains unknown.
Mitochondrial DNA Content Is Linked to Cardiovascular Disease Patient Phenotypes
Authors: Wei, Ruipeng , Ni, Ying , Bazeley, Peter , Grandhi, Sneha , Wang, Janet , Li, Samuel T. , Hazen, Stanley L. , Wilson Tang, W. H. , LaFramboise, Thomas 
Published: February 2021

Background
We sought to determine whether mitochondrial DNA (mtDNA) content can be used as markers for 12 key phenotypes among cardiovascular disease patients, and whether these markers are valid across patients with diverse ancestries.

Methods and Results

DNA was collected from the peripheral blood of 996 cardiovascular disease patients at the Cleveland Clinic. The mtDNA copy number and DNA‐level variation were assessed from whole‐genome sequence. Patients were also ascertained retrospectively for histories of 10 clinical events, as well as for maximum stenosis and extent of disease at baseline. Self‐reported race and maternal ancestry inferred from mtDNA sequence were recorded. MtDNA copy number and overall mtDNA rare variant load were significantly lower in patients with histories of various adverse clinical events, and mtDNA copy number was inversely correlated with extent of disease. Strong associations were also found between absence of rare variants in the genes
MT
‐ATP6
and
MT‐COII
and patient histories of hyperlipidemia and myocardial infarction, respectively. Importantly, associations were not ancestry dependent.

Conclusions
This study provides evidence that mtDNA copy number in circulation is associated with a variety of cardiovascular disease patient phenotypes. Results also suggest a protective role for some rare inherited mtDNA variants. Overall, the study supports the potential of mtDNA content and abundance as biomarkers in heart disease, in a manner that is valid across diverse ancestries.
Physical Pleasure and Moral Action: An Analogy in Augustine’s Thought
Authors: Knight Amanda 
Published: February 2021

Abstract
The present essay argues that Augustine’s understanding of the physical mechanism of pain and pleasure bears an analogous relationship to the internal mechanics of his moral psychology. The significance of this analogy is threefold. It corroborates emerging consensus positions regarding Augustine’s moral psychology, including recognizing the significance of Stoic influences as well as construing Augustine’s psychology as monistic; it draws attention to a greater consistency between Augustine’s earlier and later accounts of moral psychology than is typically recognized in scholarship; and it offers a schema that organizes the significant components of Augustine’s moral psychology, like his theory of action, habit, the will, and conversion, in relation to one another within a single conceptual system.
The Ilisu Dam and Its Impact on the Mesopotamian Marshes of Iraq: Implications for the Future Directions of International Water Law
Authors: Thaman Raquella Moea 
Published: February 2021

Abstract
The law of international watercourses has been successful in providing some measure of assistance in conflict avoidance and resolution. However, evolution of this body of law, which has been gradual in nature, is facing challenges adapting to climate change and its grave consequences. Climate change is causing the glaciers of the world to melt, and resulting in unpredictable shifts in patterns of rainfall, thus seriously impacting shared watercourses. The history and ecology of the Tigris Euphrates Basin, and the issues surrounding Turkey’s recent impoundment of water behind the Ilisu Dam on the Tigris, provide an example highlighting such challenges. This monograph argues that international collaboration over transboundary watercourses is imperative for maintaining peace and stability and should force us to think of new ways to address these newly emerging and growing challenges in this field.
A Climatology of Atmospheric Rivers in New Zealand
Authors: Prince Hamish D. , Cullen Nicolas J. , Gibson Peter B. , Conway Jono , Kingston Daniel G. 
Published: February 2021

AbstractThe occurrence of extreme precipitation events in New Zealand regularly results in devastating impacts to the local society and environment. An automated atmospheric river (AR) detection technique (ARDT) is applied to construct a climatology (1979–2019) of extreme midlatitude moisture fluxes conducive to extreme precipitation. A distinct seasonality exists in AR occurrence aligning with seasonal variations in the midlatitude jet streams. The formation of the Southern Hemisphere winter split jet enables AR occurrence to persist through all seasons in northern regions of New Zealand, while southern regions of the country exhibit a substantial (50%) reduction in AR occurrence as the polar jet shifts southward during the cold season. ARs making landfall on the western coast of New Zealand (90% of all events) are characterized by a dominant northwesterly moisture flux associated with a distinct dipole pressure anomaly, with low pressure to the southwest and high pressure to the northeast of New Zealand. Precipitation totals during AR events increase with AR rank (five-point scale) throughout the country, with the most substantial increase on the windward side of the Southern Alps (South Island). The largest events (rank 5 ARs) produce 3-day precipitation totals exceeding 1000 mm. ARs account for up to 78% of total precipitation and up to 94% of extreme precipitation on the west coast of the South Island. Assessment of the multiscale atmospheric processes associated with AR events governing extreme precipitation in the Southern Alps of New Zealand should remain a priority given their hydrological significance and impact on people and infrastructure.
Coupled Ocean–Atmosphere Covariances in Global Ensemble Simulations: Impact of an Eddy-Resolving Ocean
Authors: Frolov Sergey , Reynolds Carolyn A. , Alexander Michael , Flatau Maria , Barton Neil P. , Hogan Patrick , Rowley Clark 
Published: February 2021

AbstractPatterns of correlations between the ocean and the atmosphere are examined using a high-resolution (1/12° ocean and ice, 1/3° atmosphere) ensemble of data assimilative, coupled, global, ocean–atmosphere forecasts. This provides a unique perspective into atmosphere–ocean interactions constrained by assimilated observations, allowing for the contrast of patterns of coupled processes across regions and the examination of processes affected by ocean mesoscale eddies. Correlations during the first 24 h of the coupled forecast between the ocean surface temperature and atmospheric variables, and between the ocean mixed layer depth and surface winds are examined as a function of region and season. Three distinct coupling regimes emerge: 1) regions characterized by strong sea surface temperature fronts, where uncertainty in the ocean mesoscale influences ocean–atmosphere exchanges; 2) regions with intense atmospheric convection over the tropical oceans, where uncertainty in the modeled atmospheric convection impacts the upper ocean; and 3) regions where the depth of the seasonal mixed layer (MLD) determines the magnitude of the coupling, which is stronger when the MLD is shallow and weaker when the MLD is deep. A comparison with models at lower horizontal (1/12° vs 1° and 1/4°) and vertical (1- vs 10-m depth of the first layer) ocean resolution reveals that coupling in the boundary currents, the tropical Indian Ocean, and the warm pool regions requires high levels of horizontal and vertical resolution. Implications for coupled data assimilation and short-term forecasting are discussed.