bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB216: Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity
Authors: Sheppard Hadley E. , Dall'Agnese Alessandra , Park Woojun D. , Shamim Hamza , Dubrulle Julien , Johnson Hannah L. , Stossi Fabio , Cogswell Patricia , Sommer Josh , Levy Joan , Sharifnia Tanaz , Wawer Mathias J. , Clemons Paul A. , Nabet Behnam , Gray Nathanael S. , Schreiber Stuart L. , Workman Paul , Young Richard A. , Lin Charles Y.
Published: July 2021

Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Brachyury defines the chordoma super-enhancer landscape, autoregulates through binding its super-enhancer, and its locus forms a transcriptional condensate. Both transcriptional CDK inhibition and brachyury degradation disrupt brachyury autoregulation, leading to loss of its transcriptional condensate and transcriptional program. Compared with transcriptional CDK inhibition which globally downregulates transcription leading to cell death, brachyury degradation is much more selective, inducing senescence and sensitizing cells to anti-apoptotic inhibition. These data suggest that brachyury downregulation is a core tenet of transcriptional CDK inhibition and motivates developing strategies to target brachyury and its autoregulatory feedback loop.

Citation Format: Hadley E. Sheppard, Alessandra Dall'Agnese, Woojun D. Park, Hamza Shamim, Julien Dubrulle, Hannah L. Johnson, Fabio Stossi, Patricia Cogswell, Josh Sommer, Joan Levy, Tanaz Sharifnia, Mathias J. Wawer, Paul A. Clemons, Behnam Nabet, Nathanael S. Gray, Stuart L. Schreiber, Paul Workman, Richard A. Young, Charles Y. Lin. Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity [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 LB216.
Abstract LB219: Methods to improve representation of racial and ethnic minorities in lung cancer screening programs: A systematic review
Authors: Gilliard Tiffany J. , Perez-Morales Jaileene , Schabath Matthew , Haver Mary Katherine
Published: July 2021

Background: Most lung cancer screening trials to date and current screening guidelines overlook vulnerable populations with disproportionate lung cancer burden such as racial and ethnic minorities. Given the barriers, perceptions, and socioeconomic burden of these underserved populations, uptake of lung cancer screening has minimal. To develop and implement better methods of recruitment underserved populations, concerted efforts to understand the barriers and perceptions of these population are needed. Objective: Conduct a systematic review of methods for recruitment of racial and ethnic minorities into lung cancer screening trials or programs. Methods: We searched for studies that reported methods of recruitment and racial and ethnic minorities into lung cancer screening from 2010 to June 2020, using Ovid MEDLINE and Embase databases. Full-text screening and data extraction were completed independently by two reviewers and adjudication was performed by a third, independent reviewer. We compared referral rates of the recruitment modalities by racial/ethnic subgroups and by sex. Results: We identified 525 studies of which 25 were included in the systematic review corresponding to 291,329 patients. The most frequent methods of recruitment were referral, physical mail, community-based strategies, targeted strategies, phone, advertisement, and social media. Referral (n=7; 2,510 patients) was the most effective method of recruitment with response rates ranging from 31% to 97%. Direct mail (n=8 studies; 189,799 patients) was the second most extensively used recruitment method with response rates of 28% to 79%. Direct mail to Hispanic patients (2,995 total) for lung cancer screening programs was more effective than other methods of recruitment. Direct mail was more effective in recruiting African American patients (8,331 total) compared to referral (1,083 total). Conclusion: This review identified recruitment modalities that were more successful and less unsuccessful in recruiting racial and ethnic minorities into lung cancer screening trials and programs. This work highlights priorities and next steps required to improve recruitment of racial and ethnic minorities in lung cancer screening. There is a need to develop culturally relevant lung cancer screening interventions for Hispanics/Latino patients and to create targeted intervention for African American patients.

Citation Format: Tiffany J. Gilliard, Jaileene Perez-Morales, Matthew Schabath, Mary Katherine Haver. Methods to improve representation of racial and ethnic minorities in lung cancer screening programs: A systematic review [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 LB219.
Abstract LB228: PD-L1/PD-1 and arsenic lung tumorigenesis
Authors: Xu Wenhua , Chen Gang
Published: July 2021

Chronic exposure of environmental arsenic promotes lung cancer. Emerging evidence indicates that compromised host immunity, particularly T cell anti-tumor immunity, may play a critical role in cancer development. However, there is a knowledge gap in terms of the effects of arsenic exposure on T cell anti-tumor immunity and how that may contribute to arsenic lung carcinogenicity. Immunosuppression has been known as a risk factor for many types of cancer, including lung cancer. The development of cancer indicates a success of immunosuppression and escape of cancer cells from host anti-tumor immunity in which T cells are the major component. The anti-tumor immunity is mainly executed by CD8 cytotoxic T cells through their anti-tumor effector function. A/J mice are naturally sensitive to pulmonary carcinogens and prone to develop spontaneous lung tumors later in life and have been frequently used as an animal model for lung tumorigenesis research. Chronic arsenic administration through drinking water has been shown to enhance tumor formation in the lungs of A/J mice. In the current study, using this mouse model we determined that prolonged arsenic exposure up-regulated PD-1/PD-L1, inhibited T cell antitumor function and enhanced lung tumor formation, while inhibition of PD-1/PD-L1 restored T cell anti-tumor effector function and mitigated arsenic-enhanced lung tumorigenesis. In addition, inhibition of PD-1/PD-L1 could be a preventive approach to mitigate tumorigenic action of chronic arsenic exposure.

Citation Format: Wenhua Xu, Gang Chen. PD-L1/PD-1 and arsenic lung tumorigenesis [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 LB228.
Abstract LB232: Imbalance of TGF-β1/BMP-7 pathway induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness
Authors: Ning Junya , Ye Yingnan , Yu Jinpu
Published: July 2021

The transforming growth factor-beta (TGF-β) signaling represented the predominant cytokine signaling involved in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of TGF-β superfamily, was frequently found to have cross-talk with TGF-β pathway. However, the complex interaction between TGF-β and BMP pathways has not been fully elucidated in HCC. In this study, we found that the imbalance of TGF-β1/BMP-7 pathway was associated with aggressive pathological features and poor clinical outcome in HCC, and it could significantly promote HCC cells invasion and stemness by increasing inhibitor of differentiation 1 (ID1). Next, we indicated that the miR-17-92 cluster could disrupted the balance of TGF-β1/BMP-7 pathway in HCC cells by inducing TGFBR2 post-transcriptional silence and inhibiting ACVR1 post-translational ubiquitylation via targeting Smurf1. Furthermore, we demonstrated that miR-17-92 cluster was originated from the extracellular vesicles (EVs) of M2-polarized tumor associated macrophages (M2-TAMs) infiltrated in HCC microenvironment and induced the imbalance of TGF-β1/BMP-7 pathway. Finally, we found that sh-MIR17HG lentivirus, TGFBR2 lentivirus and ACVR1 inhibitor could profoundly inhibit M2-TAMs-stimulated the growth and metastasis of HCC xenografts in vivo. We propose that imbalance of TGF-β1/BMP-7 pathway may serve as a prognostic biomarker, M2-TAMs and miR-17-92 cluster could be a therapeutic target for this subtype of HCC.

Citation Format: Junya Ning, Yingnan Ye, Jinpu Yu. Imbalance of TGF-β1/BMP-7 pathway induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness [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 LB232.
Abstract LB246: E-cadherin loss drives Id2-dependent dampening of cell cycle progression and predicts increased susceptibility to CDK4/6 inhibition in lobular breast cancer
Authors: Rätze Max Antonius Klaus , Koorman Thijs , Sijnesael Thijmen , Bassey-Archibong Blessing , van de Ven Robert , Enserink Lotte , Visser Daan , Jaksani Sridevi , Bakker Elvira , Richard François , Tutt Andrew , Steele Rebecca , Pettitt Stephen , Lord Christopher J. , Fitzpatrick Amanda , Isacke Clare , van Diest Paul J. , Desmedt Christine , Daniel Juliet M. , Derksen Patrick W.B.
Published: July 2021

Invasive lobular breast carcinoma (ILC) is a low grade and mostly chemo-refractory luminal-type breast cancer that has been linked to sustained proliferative quiescence and long-term latency relapses (15-20 years). Loss of E-cadherin causes metastatic lobular breast cancer, partly through acquisition of anchorage independence. It is however still unknown how ILC cells control the balance between proliferative indolence and cell cycle re-entry at the metastatic site. We show here that E-cadherin loss leads to upregulation of Id2 through p120-catenin/Kaiso-dependent transcriptional derepression. Anchorage independent conditions further exacerbate p120-driven Id2 expression, leading to a sustained G0/G1 cell cycle arrest through binding of cytosolic Id2 to hypo-phosphorylated Rb. Intriguingly, we find that E-cadherin inactivation causes increased sensitivity to CDK4/6 inhibition in mouse and human breast cancer cell lines and primary tumor organoids. Finally, we find that Id2 expression is elevated in human ILC when compared to ductal breast cancers. Based on these data, we propose that combined E-cadherin loss and cytosolic Id2 expression can be used for the differential diagnosis of ILC and represent a candidate predictive biomarker pair for cell cycle targeting drug efficacy.

Citation Format: Max Antonius Klaus Rätze, Thijs Koorman, Thijmen Sijnesael, Blessing Bassey-Archibong, Robert van de Ven, Lotte Enserink, Daan Visser, Sridevi Jaksani, Elvira Bakker, François Richard, Andrew Tutt, Rebecca Steele, Stephen Pettitt, Christopher J. Lord, Amanda Fitzpatrick, Clare Isacke, Paul J. van Diest, Christine Desmedt, Juliet M. Daniel, Patrick W.B. Derksen. E-cadherin loss drives Id2-dependent dampening of cell cycle progression and predicts increased susceptibility to CDK4/6 inhibition in lobular breast 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 LB246.
Abstract LB261: BRAF inhibitor reprograms cancer-associated fibroblasts to elicit matrix remodeling and therapeutic escape in melanoma
Authors: Liu Tianyi , Zhou Linli , Zhang Yuhang
Published: July 2021

The tumor stroma and its cellular components are known to play important roles in tumor resilience towards treatment but remain to be urgently characterized in melanoma targeted therapy. By performing a paired-analysis of melanoma tissue samples collected from the patients before and after combined BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) treatment, we discovered that the number of intratumoral cancer-associated fibroblasts (CAFs) increased significantly in BRAFi/MEKi-treated melanoma stroma comparing with the samples before the therapy. Those intratumoral CAFs exhibit increased amounts of nuclear β-catenin under BRAFi/MEKi therapy. Further studies show that BRAFi not only leads to increased β-catenin nuclear accumulation in CAFs and enhances their biological properties, suggesting BRAFi induces a new resistant phenotype in CAFs. In both in vitro and in vivo models, depleting β-catenin in CAFs abolishes their ability to elicit melanoma cell growth and drug resistance. BRAFi induces BRAF and CRAF dimerization and subsequently the activation of MEK/ERK signaling in CAFs, leading to the inactivation of the β-catenin destruction complex. RNA-Seq data reveals that nuclear β-catenin is a major regulator of CAF phenotype. We identify matricellular protein periostin (POSTN) as a downstream effector of β-catenin. In melanoma, POSTN is uniquely expressed in CAFs, and BRAFi can specifically upregulate POSTN production in CAFs but not in melanoma cells. Recombinant POSTN contributes to melanoma cell BRAFi/MEKi resistance and can compensate for the loss of β-catenin in CAFs. By reactivating ERK pathway in melanoma cells through PI3K/AKT signaling, POSTN compensates for the loss of β-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. In summary, our data reveal a novel resistance mechanism in melanoma that is elicited by BRAFi-induced non-canonical nuclear β-catenin signaling in CAFs and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma.

Citation Format: Tianyi Liu, Linli Zhou, Yuhang Zhang. BRAF inhibitor reprograms cancer-associated fibroblasts to elicit matrix remodeling and therapeutic escape in melanoma [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 LB261.
Abstract NG06: Addressing scaffolding roles of oncogenic kinases with targeted protein degradation
Authors: Burslem George
Published: July 2021

Proteolysis Targeting Chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of proteins. PROTACs are heterobifunctional small molecules which co-opt the ubiquitin proteasome system to destroy oncogenic proteins. The development of PROTACs for receptor tyrosine kinases (EGFR, Her2 and c-MET), a protein family previously thought to be intractable for induced protein degradation, will be described. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone including more potent inhibition of cell proliferation, a more durable and sustained downstream signaling response. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach. Application of the PROTAC technology to targets, including RTKs, in hematological malignancies has also provided potential therapeutic approaches and enhanced understanding of scaffolding roles of oncogenic kinases. The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, traditional small molecule inhibitors suffer from limited efficacy in the clinic. A FLT-3 targeting PROTAC with sub-nanomolar antiproliferative activity and the ability to induce tumor regression in vivo will be described. Additionally, the discovery of apoptosis suppression as a kinase independent activity of FLT-3 ITD will be described. While the use of kinase inhibitors of oncoprotein BCR-Abl have enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. An allosteric BCR-Abl PROTAC demonstrates significant advantages compared to inhibition and identified scaffolding roles for BCR-Abl which are not addressed by inhibitors but can be abrogated by protein degradation. Concurrent treated with the allosteric PROTAC and orthosteric inhibitors proved synergistic, particularly against some clinically relevant BCR-Abl kinase domain mutants. Furthermore, investigation into the kinase independent roles of BCR-Abl in patient stem cells suggest that these persistent leukemic stem cells are BCR-Abl agnostic.

Citation Format: George Burslem. Addressing scaffolding roles of oncogenic kinases with targeted protein degradation [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 NG06.
Abstract PL02-02: Harnessing the value of mutational signatures in whole cancer genomes
Authors: Nik-Zainal Serena
Published: July 2021

Mutational signatures are the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis. They are biologically informative, reporting on the processes that have contributed to the developmental history of each patient's cancer. In this lecture, on behalf of my team and my collaborators, I shall provide an update on the field, focusing on validation of these abstract mathematical concepts, untangling the mechanisms underpinning mutation patterns in human somatic cells, and describing the new insights that we have gained through combinations of computational analysis and experiments in cell-based systems. We showcase how mutational-signature-based clinical algorithms have been developed, describe the path taken in translating these towards medical utility and for balance, highlight some of the hurdles that need to be navigated in this type of translational research.

Citation Format: Serena Nik-Zainal. Harnessing the value of mutational signatures in whole cancer genomes [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 PL02-02.
Abstract PL04-02: Targeting regulatory T cells in cancer: From mechanisms to new therapies
Authors: Quezada Sergio
Published: July 2021

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

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

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

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

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.
Erythropoietin-Resistant Anemia Secondary to Zinc-Induced Hypocupremia in a Hemodialysis Patient
Authors: Munie Stephanie , Pintavorn Pairach
Published: July 2021

Excessive intake of zinc is a known but often forgotten cause of copper deficiency, and its consequences in the context of end-stage renal disease (ESRD) are not widely discussed. Zinc-induced copper deficiency (ZICD) can result in erythropoietin (EPO)-resistant anemia and may not be considered as a possible etiology when conducting the work-up. We present a case wherein an ESRD patient had been receiving excess zinc for several months and subsequently experienced EPO-resistant anemia. Our patient’s GI work-up was negative, and increased doses of iron and EPO-stimulating agent were ineffective. She underwent a bone marrow biopsy and more serological testing. She was ultimately diagnosed with ZICD, and cessation of her zinc supplement and initiation of copper replacement proved effective in restoring EPO responsiveness. Awareness of ZICD as a possible factor in EPO-resistant anemia could lead to an expedited diagnosis and avoid an unnecessary and extensive work-up.
The Importance of Early Detection of Genetic Diseases
Authors: Varghese Suma Elcy , El Otol Rana Hassan Mohammad , Al Olama Fatma Sultan , Elbadawi Salah Ahmad Mohamed
Published: July 2021

Background: Early detection of diseases in newborn may help in early intervention and treatment, which may either cure the disease or improve the outcome of the patient. Dubai’s Health Authority has a newborn screening program which includes screening for metabolic and genetic conditions, for hearing and vision, and for congenital heart disease. Objectives: The objectives of this study are to assess the outcome of the newborn genetic screening program, to correlate the association between the outcome of the program and demographic variables and to find out the percentage of the number of infants who were confirmed to have the genetic disease (by confirmatory tests) out of the total infants who had positive screening test results. Methods: During the period of the study from January 2018 to December 2018, a total of 7,027 newborns were tested in Dubai Health Authority facilities by the newborn genetic screening program (known as the “Step One Screening”). Blood samples were collected by heel prick on a collection paper. All samples were transported to PerkinElmer Genomics in the USA where the tests were done. The genetic disorders identified were correlated with different variables like gender and nationality. The data were entered in an excel sheet and analyzed by using SPSS software. All infants aged 0–3 months who have done newborn genetic screening at Dubai Health Authority facilities between January and December 2018 were included. Results: The incidence of screened disorders was 1:7,027 for congenital adrenal hyperplasia, 1:1,757 for congenital hypothyroidism, 1:1,757 for inborn errors of metabolism, 1:2,342 for biotinidase deficiency, 1:1,171 for hemoglobinopathies, 1:12 for hemoglobinopathy traits, and 1:10 for different genetic mutations of G6PD deficiency. Conclusions: There is a high incidence of different genetic diseases detected by newborn screening. These results justify unifying the program in the UAE and preventive programs like premarital screening and genetic counseling.
Clue of Diagnosis for Autoimmune Gastritis
Authors: Nishizawa Toshihiro , Yoshida Shuntaro , Watanabe Hidenobu , Toyoshima Akira , Kataoka Yosuke , Takahashi Yoshiyuki , Kanazawa Takamitsu , Ebinuma Hirotoshi , Suzuki Hidekazu , Koike Kazuhiko , Toyoshima Osamu
Published: July 2021

Background: The diagnostic clues for autoimmune gastritis (AIG) can be classified into 2 categories: endoscopic findings and pathological diagnosis. We believe that research on the AIG detection rate by endoscopists could provide a better understanding of the diagnosis of AIG. This study aimed to clarify the ratio of the endoscopic and the pathological diagnoses of AIG. Methods: We retrospectively reviewed consecutive patients who underwent esophagogastroduodenoscopy (EGD). During their first EGD, the gastric mucosa with C2 atrophy or more was biopsied for pathological evaluation based on the updated Sydney system. A gastric biopsy was also performed after Helicobacter pylori eradication, obtaining specimens from at least 2 sites, the greater curvature of the corpus and the antrum. We enrolled patients who were positive for the anti-parietal cell antibody and were diagnosed with AIG, histologically and/or endoscopically. The detection rates of AIG were compared between endoscopic diagnosis and pathological diagnosis. Results: A total of 10,822 patients underwent EGD during the study period. Finally, 41 patients with AIG were enrolled, leading to an AIG prevalence of 0.38% in this study. As for the clue leading to AIG detection, 31.7% (13/41) were diagnosed through endoscopy (proximal-predominant atrophy), and 68.3% (28/41) were diagnosed pathologically. The AIG detection rate by endoscopists in the posteradication group was significantly lower than in the H. pylori-negative group (p < 0.05). Conclusion: Endoscopists frequently overlooked AIG, especially in posteradication cases. Pathological assessment using the updated Sydney system after H. pylori eradication might be a promising strategy to detect AIG better.
Microscope-Assisted Episcleral Surgery with Encircling Buckles and Chandelier Endoillumination for Primary Rhegmatogenous Retinal Detachment in Phakic and Pseudophakic Patients: A 12-Month Comparative Study
Authors: Alkabes Micol , Fogagnolo Paolo , Vezzola Diego , Muraca Andrea , Savoini Alberto , Wild Davide , Frerio Filippo , Ranno Stefano , Radice Paolo , De Cillà Stefano
Published: July 2021

Introduction: The aim of the study was to compare postoperative outcomes after microscope-assisted encircling buckle and chandelier endoillumination for primary rhegmatogenous retinal detachment (RRD) in phakic and pseudophakic (PFK) patients. Methods: 121 eyes of 117 patients were divided into 2 groups depending on the lens status (group 1, PFK, 53 eyes; group 2, phakic, 68 eyes). The main outcomes include retinal reattachment rate (RRR) and best-corrected visual acuity (BCVA) at 1 week, 1, 3, 6, and 12 months. Results: The overall primary RRR was 91.7% (111/121). In group 1, the primary RRR was 90.6% (48/53), whereas in group 2 it was 92.6% (63/68). The mean preoperative BCVA improved in both groups at 12 months. Undetected retinal breaks were found in 9.9% of cases. When an encircling 5-mm oval sponge was used, no additional exoplants were required and transcleral drainage was performed in 89.7% of the eyes. In group 1, among the 5 PFK eyes with persistent RRD, 4 eyes had a sulcus intraocular lens. Conclusions: Microscope-assisted episcleral surgery with chandelier endoillumination is an effective technique for primary RRD in both phakic and PFK eyes with uncomplicated cataract surgery. Chandelier endoilluminators help to visualize undetected retinal breaks, especially in PFK eyes. In case of a circumferential 5-mm oval sponge, additional exoplants are not required and transcleral drainage is strongly recommended to flatten the retina by closing the causative breaks.
Jesus’s Trinity?
Authors: Keener Craig
Published: July 2021

Multiple independent sources from within living memory report that Jesus taught his disciples, shortly before or after his resurrection, that he was divine and that the divine Spirit could be distinguished from him and from the Father. These sources cohere well and suggest that later affirmations that God is Father, Son, and Spirit develop material that goes back to the earliest period of Christian faith.
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.
Pro-Regime Posters in the Democratic Republic of Afghanistan
Authors: Kłagisz Mateusz M. P.
Published: July 2021

The article discusses three Afghan posters as a source of information on the political system between 1978 and 1992 and its internal dynamics. The posters are an integral part of Afghan visual culture and at the same time they are an inseparable element of the broader propaganda culture developed by communist parties. Consequently, such categories as unity, utility and wishful thinking characteristic for the socialist realist art and propaganda put the posters in the broadly understood phenomenon of Orwellian newspeak. To discuss their Orwellian dimension theoretical tools developed by Umberto Eco have been applied.
Michael Tierney and the Intellectual Origins of Blueshirtism, 1920–1938
Authors: Donnelly Seán
Published: July 2021

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.
Rhamnidium riograndense (Rhamnaceae), a new species from southern Brazil
Authors: FIGUEIRA MAURÍCIO , SCHINDLER BIANCA
Published: July 2021

A new species, Rhamnidium riograndense, from southern Brazil, is here described and illustrated. We present information about its distribution, habitat, phenology, conservation status and a key for all the South American species of the genus is provided. The new species is endemic to the central part of the state of Rio Grande do Sul, in the transition between Paraná and Pampean provinces in rocky habitats, mostly mountain slopes, where only four populations are currently known.
Lectotypification of the name Carex setosa (Cyperaceae)
Authors: GHOSH ASOK
Published: July 2021

Carex setosa Boott is a highly variable Sino-Himalayan species. In the protologue, the species was described by Francis Boott with three distinct morphotypes. Morphotypes were further illustrated in three different tabs. J.D. Hooker collected all the morphotypes in Lachen, Sikkim in 1849. The Indian morphotypes are Carex setosa var. setosa. The name Carex setosa is lectotypified here.
The family Lecithoceridae (Lepidoptera, Gelechioidea) from Bioko Island (Equatorial Guinea), with descriptions of five new species
Authors: PARK KYU-TEK , KARISCH TIMM
Published: July 2021

Five new species belonging to the subfamily Torodorinae of Lecithoceridae are described from Bioko Island (Equatorial Guinea), based on specimens which were collected during a short expedition on the island by the second author in 1994. The new species are three species of the genus Thubdora Park, 2018 (T. biocoica sp. nov., T. vernaculella sp. nov., and T. angustiala sp. nov.), and a new species of Ptilothyris Walsingham, 1891and Dragmatucha Meyrick, 1908 respectively (Ptylothyris ruicheensis sp. nov.; and Dragmatucha vulcaniella sp. nov.). In addition, Thubdora bilobella Park, 2018 is reported for the first time from Equatorial Guinea. Images for adults and the genitalia of all species are given.
A new species of Thoropa Cope, 1865 (Anura, Cycloramphidae) from the Serra da Mantiqueira, Southeast Brazil
Authors: ASSIS CLODOALDO LOPES , LACERDA JOÃO VICTOR A. , GUIMARÃES CARLA SILVA , PEIXOTO MARCO ANTÔNIO , LUNA MARIA CELESTE , FEIO RENATO NEVES
Published: July 2021

We describe a new species of Thoropa, previously identified as T. lutzi, from the northern region of the Serra da Mantiqueira in the Atlantic Forest domain in Southeast Brazil. The new species is diagnosed by the following combination of characters: small size; slender body; head longer than wide; dark colored nuptial pads on the inner side of the Finger I and on the internal carpal tubercle; nuptial pads with epidermic cone-shaped papillae measuring of 53.1–91.6 μm in diameter, and at a density of 14–32 papillary epidermic projections/mm2; presence of vocal sac and vocal slits; and advertisement call with 5–10 harmonics, duration of 0.23–0.42 s, and peak of frequency of 2060–4470 Hz. With the description of the new species, T. lutzi is now only known for the state of Rio de Janeiro.
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.
Screening and validation of genome-edited animals
Authors: Bunton-Stasyshyn Rosie K , Codner Gemma F , Teboul Lydia
Published: July 2021

The emergence of an array of genome-editing tools in recent years has facilitated the introduction of genetic modifications directly into the embryo, increasing the ease, efficiency and catalogue of alleles accessible to researchers across a range of species. Bypassing the requirement for a selection cassette and resulting in a broad range of outcomes besides the desired allele, genome editing has altered the allele validation process both temporally and technically. Whereas traditional gene targeting relies upon selection and allows allele validation at the embryonic stem cell modification stage, screening for the presence of the intended allele now occurs in the (frequently mosaic) founder animals. Final confirmation of the edited allele can only take place at the subsequent G1 generation and the validation strategy must differentiate the desired allele from a range of unintended outcomes. Here we present some of the challenges posed by gene editing, strategies for validation and considerations for animal colony management.