bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL04-02: Targeting regulatory T cells in cancer: From mechanisms to new therapies
Authors: Quezada Sergio 
Published: July 2021

Abstract
Regulatory T cells have a critical role in the maintenance of immune homeostasis in mice and man. However, despite their role in maintaining host integrity, their function is known to be hijacked in the context of cancer. The murine and human tumour microenvironment actively recruits regulatory T cells bearing features of activation such as upregulation of the high affinity IL2Ra (CD25) and the immune-regulatory receptor CTLA-4. In mice, anti-CTLA-4 antibodies are able to promote depletion of Tregs and enhanced tumour control whilst in humans this remains less clear. That said, in human cancers, the number of tumour infiltrating regulatory T cells and their spatial distribution with regards to effector T cells has been negatively associated to patient outcomes, underscoring their negative role in anti-tumour immunity and the need for tools that tamper with their function and number. In this talk I will discuss the role of regulatory T cells in the context of cancer, as well as old and new strategies to target this compartment including the development of a new CD25-targeting Treg depleting antibody for mice and man.
Citation Format: Sergio Quezada. Targeting regulatory T cells in cancer: From mechanisms to new therapies [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 PL04-02.
Abstract SY07-02: Gaining biologic insights into glioblastoma using proteomics
Authors: Barnholtz-Sloan Jill S. 
Published: July 2021

Abstract
Glioblastoma (GBM) is the most common type of primary malignant tumor in adults and contributes disproportionately to cancer morbidity and mortality. Understanding its molecular pathogenesis is crucial for improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomics data on 99-treatment naïve GBMs provided insights to GBM biology. Multiple key findings emerged that were not known from traditional genomic analyses: (1) Analysis of protein phosphorylation identified key signaling intermediates in the RTK/RAS path-way common to multiple RTK genomic alterations (PTPN11 and PLCG1), potentially offering common therapeutic targets for different oncogenic drivers in GBM. (2) Phosphoproteomics also identified potential druggable targets based on kinase-substrate pathway analysis, as well as novel phosphoprotein targets associated with the regulation of telomere length by ATRX in IDH mutants. (3) TP53 protein abundance in GBM is regulated by protein/phosphoprotein effectors (4) Four immune GBM subtypes exist, characterized by distinct immune cell population differences – Immune High and Immune Low phenotypes in GBM were driven by tumor-associated macrophage markers, and associated with distinct epigenetic modifications and histone acetylation patterns. (5) The mesenchymal subtype displays EMT signatures specific in tumor cells, distinct from infiltrating immune cells. (6) Histone H2B acetylation and immune-low GBM was driven largely by BRDs, CREBBP, and EP300. (7) Identification of key metabolic changes in IDH mutants facilitating the accumulation of onco-metabolite 2-HG were also associated with lipidomic changes. This work identifies additional therapeutic channels for GBM and novel information useful for more accurate stratification patients for effective treatment.
Citation Format: Jill S. Barnholtz-Sloan. Gaining biologic insights into glioblastoma using proteomics [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 SY07-02.
Abstract SY20-01: USP18 modulates the ISGylome immune signaling, and sensitizes tumor cells to irradiation and CTL recognition
Authors: Kessler Benedikt 
Published: July 2021

Abstract
Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models. Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.
Citation Format: Benedikt Kessler. USP18 modulates the ISGylome immune signaling, and sensitizes tumor cells to irradiation and CTL recognition [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 SY20-01.
Abstract SY30-02: NK cells remember: Engineering NK cell memory-like responses for cancer immunotherapy
Authors: Fehniger Todd A. 
Published: July 2021

Abstract
Natural killer (NK) cells are innate lymphoid cells that protect against infection and mediate anti-tumor immune responses. NK cell immunotherapy is a promising cellular therapy approach for leukemia, lymphoma, and other cancers. Multiple laboratories have advanced our understanding of innate NK cell memory and memory-like responses over the past decade, with a unifying definition of enhanced response to re-stimulation after an initial activation event. We identified that human cytokine-induced memory-like (memory) NK cells differentiate after a brief activation with IL-12, IL-15, and IL-18 and mediate enhanced responses against leukemia and other cancer targets. Pre-clinical studies have demonstrated their enhanced anti-tumor potential in vitro, and in vivo in syngeneic murine models and human xenografts. We translated this concept into a first-in-human clinical trial that demonstrated safe adoptive transfer of donor memory NK cells for patients with relapsed or refractory acute myeloid leukemia (AML) resulting in complete remissions. Correlative mass cytometry from this phase 1 study revealed the memory NK cell multidimensional phenotype and identified NKG2A as a major checkpoint for memory NK cell response to AML. Additional clinical trials of donor memory NK cells the HCT setting have demonstrated safety and anti-leukemia activity the immune compatible setting and has provided insights into persistence. Memory NK cells functionally persist for more than 60 days with a unique multidimensional phenotype in two clinical trials in leukemia patients. Further, CITE-seq single cell profiling reveals a unique memory NK cell transcriptomic signature. We have also developed approaches to gene edit and engineer memory-like NK cells with chimeric antigen receptors, expanding the spectrum of cancers for memory-like NK cellular therapy. CAR memory NK cells exhibit enhanced responses, compared with CAR conventional NK cells. Further, pairing with tumor targeting monoclonal antibodies can result in CAR-like responses via CD16/FcγRIIIa, providing additional activating signals that direct memory NK cell response. These studies identify a promising memory NK cell platform for cancer immunotherapy and highlight the importance of correlative studies during clinical trials to advance our understanding of human immunology.
Citation Format: Todd A. Fehniger. NK cells remember: Engineering NK cell memory-like responses for cancer immunotherapy [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 SY30-02.
Abstract SY42-02: Stem cell clonality and the niche
Authors: Zon Leonard I. 
Published: July 2021

Abstract
Hematopoietic stem cell transplantation involves the homing of stem cells to the marrow, an active process of engraftment, and the self-renewal of the blood stem cells. We have been using the zebrafish as a model to study the molecular biology of this process. Blood stem cells are born in the dorsal aorta of the developing embryo. By imaging RUNX1 GFP+ cells arriving in the next site of hematopoiesis (the caudal hematopoietic territory), engraftment can be visualized. The endothelial cells of the niche cuddle the hematopoietic stem cells, and the stem cells divide in the niche. We have used RNA tomography to find transcripts that are restricted in expression to the niche endothelial cells. After sorting these endothelial cells, we used ATAC seq to reveal regions of chromatin that are open. The regions function in enhancer assays to drive expression of GFP in the niche. By computing the binding sites in these regions, and examining RNA seq, we found transcription factors that may participate in niche endothelial development. Overexpression of three of these transcription factors is sufficient to reprogram embryonic cells to express the markers of the niche. New niches form in ectopic locations and HSPCs arrive in the new niche, akin to extramedullary hematopoiesis, are cuddled by endothelial cells and divide. Using a brainbow color barcoding system, we previously demonstrated that zebrafish produce 20-30 HSCs from the developing aorta. HSCs traffic to the embryonic niche where they exit circulation and divide. To evaluate a possible role of macrophages in attenuating HSC clone number, we depleted macrophages in our brainbow barcoding system. Unique color barcodes were induced in individual HSCs at 24 hpf, just prior to stem cell emergence, and clodronate loaded liposomes injected into circulation. On average, animals injected with clodronate liposomes had only 14 HSC color clones, compared to 24.6 HSC clones in sibling controls (p = 0.0002). Our studies show that there is a transcriptional code for niche endothelial cells and that macrophages are required for establishing clonality.
Citation Format: Leonard I. Zon. Stem cell clonality and the niche [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 SY42-02.
Lambdacism and the Development of Old Iranian *tin Pashto
Authors: Kreidl Julian 
Published: July 2021

It is a well-known fact that Pashto belongs to those Eastern Iranian languages, which show lambdacism. While similarities exist with Bactrian and Munji-Yidgha, the situation in Pashto is not exactly the same, and is in any case far more complicated. Especially interesting in this respect is the development of Old Iranian *t, which is sometimes shifted to l in Pashto proper and y in Waneci, sometimes yields the voiced dental d, or, as a third outcome, disappears in all varieties.
In this paper, it is argued that the first lambdacism of (Old Iranian *d >) *δ > l, in the early first millennium A.D., spread from Bactrian, the prestigious lingua franca of the Kushan and subsequent Empires, into the contemporary ancestors of Munji(-Yidgha), Pashto and Prasun. Almost a millennium later, there was another, geographically far more limited lambdacism. This time, one subgroup of Pashto from which all Pashto proper dialects would emerge, changed, at least in certain environments, (Old Iranian *t >) *d > *δ to l, while it was changed to a palatal glide in Waneci. In other phonological environments, *d had disappeared before it could be shifted to l and y, respectively, and left no traces in contemporary dialects. In those cases where *t corresponds to d in all contemporary varieties of Pashto, we are dealing with a secondary restoration of the dental or sandhi, which lead to a voicing of initial *t.
Michael Tierney and the Intellectual Origins of Blueshirtism, 1920–1938
Authors: Donnelly Seán 
Published: July 2021

Abstract
The Blueshirts have been one of the most contested and extensively researched subjects in twentieth-century Irish historiography. Debate has focused principally on the extent to which the movement should be understood as a fascist organisation, or as a spontaneous counter-reaction to the domestic political instability that followed Fianna Fáil’s victory in the 1932 general election. However, strikingly little attention has been devoted to tracing the intellectual origins of Blueshirtism in Irish nationalist and republican thought. This article rejects the dominant historiographical representation of the Blueshirts as an aberration in Irish political history and suggests that the movement can only be understood properly in continuity with the political thought of the pre-Civil War period. It is argued, additionally, that the more complex and differentiated ‘hybrid’ theories of ‘fascistization’ developed by scholars like David D. Roberts, António Costa Pinto and Aristotle Kallis provide a useful comparative framework for understanding how nationalist intellectuals such as Michael Tierney, once steadfast in their commitment to the norms of parliamentary democracy, came to endorse a corporatist politics after being voted out of office.
Cost-Effectiveness of Open vs. Endoscopic Repair of Zenker’s Diverticulum
Authors: Lee Paul B. , Hojjat Houmehr , Lucas Jordyn , Chung Michael T. , Spillinger Aviv , Meleca Joseph B. , Svider Peter , Shkoukani Mahdi , Johnson Andrew , Folbe Adam 
Published: July 2021

Objective: To evaluate the cost-effectiveness of open versus endoscopic surgical repair of Zenker’s diverticulum. Methods: In this study, an economic decision tree was utilized to compare the cost-effectiveness of open surgery compared to endoscopic surgery. The primary outcome in this analysis was the incremental cost-effectiveness ratio (ICER) that was calculated based on the economic decision tree. The probability of post-operative esophageal perforation complications, revision rates, and effectiveness of each procedure along with associated costs were extracted to construct the decision tree. Univariate sensitivity analysis was then utilized to determine how changes in esophageal perforation rate affect the cost-effectiveness of each surgical approach. Results: The ICER of open surgery for Zenker’s diverticulum was $67 877, above most acceptable willingness to pay (WTP) thresholds. Additionally, if the probability of esophageal perforation with endoscopic surgery is above 5%, then open surgery becomes a more cost-effective option. Probabilistic sensitivity analysis using Monte Carlo simulations also showed that at the WTP thresholds of $30 000 and $50 000, endoscopic surgery is the most cost-effective method with 83.9% and 67.6% certainty, respectively. Conclusion: Open surgery and endoscopic surgery are 2 treatment strategies for Zenker’s diverticulum that each have their own advantages and disadvantages that can complicate the decision-making process. With no previous cost-effectiveness analysis of open versus endoscopic surgery for Zenker’s diverticulum, our results support the endoscopic approach at most common WTP thresholds. Particularly with the current focus on rising healthcare costs, our results can serve as an important adjunct to medical decision-making for patients undergoing treatment for Zenker’s diverticulum.
Empowering Nurses: Communicating Potential Medication Misuse
Authors: Carlson Kelly A. , Potter Corey E. 
Published: July 2021

BACKGROUND In nursing education and practice, we prepare nurses on topics such as patient care, pathophysiology, pharmacology, nursing leadership, and nursing competencies. Unfortunately, we may be missing the mark when it comes to integrating these topics and applying them to situations that arise in health care such as medication misuse. Nurses work intimately with patients and can recognize potential medication misuse by reviewing medication regimens and assessing necessity of PRN patient requests. In cases where nurses suspect misuse, they may or may not feel comfortable addressing these concerns with other members of the health care team. AIMS Study aims were to assess the baseline of whether nurses are comfortable with their level of skill to recognize potential patient medication misuse and to assess nurses’ comfortability with communicating these concerns with other nurses, providers, and patients. METHODS This survey study was designed to obtain practical information about nurses understanding of misused and diverted prescription medications and level of comfort with expressing concerns about the use of central nervous system depressants to inform education, practice, and research. Three-hundred and fifty nurses at one hospital were invited to participate in an anonymous REDCap survey. RESULTS Thirty-five percent of the surveyed nurses returned the survey. Responding nurses were more comfortable sharing their own knowledge and the need for more education on the topic than they were discussing interdisciplinary communication. CONCLUSIONS Empowering nurses to communicate this knowledge with others on the health care team has major public health implications to reduce the negative outcomes of misused medications.
Arthroscopic Distal Tibial Allograft for Posterior Glenoid Reconstruction
Authors: Hoyt Benjamin W. , Riccio Cory A. , LeClere Lance E. , Kilcoyne Kelly G. , Dickens Jonathan F. 
Published: July 2021

Background: Posterior glenoid bone loss occurs in more than two-thirds of patients with posterior glenohumeral instability, with 14% to 22% having greater than subcritical bone loss (13.5%), a marker for potential need for bony augmentation versus soft tissue-only procedures. Several techniques are described to augment either the version or volume of the glenoid surface including osteotomies, autograft transfers, and allograft tibia transfers. Indications: Arthroscopic-assisted allograft distal tibia bone block augmentation to the posterior glenoid is indicated for revision posterior instability procedures with posterior bone loss and in primary cases of posterior instability with critical bone loss. Technique Description: Arthroscopic posterior glenoid reconstruction with allograft distal tibia and posterior labral repair in the lateral position is presented. This technique uses standard instrument sets and requires no patient repositioning. The preplanned tibial bone block is prepared on a back table either prior to, or concurrently with, arthroscopic procedure. After creation of high posterior portal and standard anterior portal, a sucker-shaver and burr are used to create a perpendicular edge for apposition of the allograft tibia. The bone block is introduced through a longitudinal incision and underdelivered to the prepared surface under the liberated labrum. The articular surface of the graft and glenoid are aligned and cannulated screws are used to compress the bone block against the native glenoid. The posterior labral tissue is then mobilized over the graft and repaired to the native glenoid. Results: Arthroscopic distal tibial allograft augmentation for posterior bone loss restored stability and function in a small cohort of patients. Patients reported improved stability in the immediate postoperative course, with restoration of motion by 2 months. Push-ups, pull-ups, and return to full active duty without restrictions is allowed at 6 months postoperatively. Imaging at 3 months postoperatively has shown excellent graft healing. Discussion: The benefits of allograft tibia augmentation for posterior instability with glenoid bone loss include an anatomic joint surface restoration including articular cartilage, lack of donor site morbidity, and a minimally invasive approach. When performed arthroscopically, this technique permits concurrent posterior labral repair and anatomic reconstruction.
Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes
Authors: Khandelwal Sanjay , Barnes Ayiesha , Rauova Lubica , Sarkar Amrita , Rux Ann H. , Yarovoi Serge V. , Zaitsev S. Sergei , Lambris John D. , Myoung Sooho S. , Johnson Alexandra , Lee Grace M. , Duarte Madelaine , Poncz Mortimer , Arepally Gowthami M. , Cines Douglas B. 
Published: July 2021

AbstractHeparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by ultra-large immune complexes (ULICs) containing immunoglobulin G (IgG) antibodies to a multivalent antigen composed of platelet factor 4 and heparin. The limitations of current antithrombotic therapy in HIT supports the need to identify additional pathways that may be targets for therapy. Activation of FcγRIIA by HIT ULICs initiates diverse procoagulant cellular effector functions. HIT ULICs are also known to activate complement, but the contribution of this pathway to the pathogenesis of HIT has not been studied in detail. We observed that HIT ULICs physically interact with C1q in buffer and plasma, activate complement via the classical pathway, promote codeposition of IgG and C3 complement fragments (C3c) on neutrophil and monocyte cell surfaces. Complement activation by ULICs, in turn, facilitates FcγR-independent monocyte tissue factor expression, enhances IgG binding to the cell surface FcγRs, and promotes platelet adhesion to injured endothelium. Inhibition of the proximal, but not terminal, steps in the complement pathway abrogates monocyte tissue factor expression by HIT ULICs. Together, these studies suggest a major role for complement activation in regulating Fc-dependent effector functions of HIT ULICs, identify potential non-anticoagulant targets for therapy, and provide insights into the broader roles of complement in immune complex–mediated thrombotic disorders.