bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY17-03: Reimagining druggability using chemoproteomic platforms
Authors: Nomura Daniel K. 
Published: June 2022

Abstract
The Nomura Research Group is focused on reimagining druggability using chemoproteomic platforms to develop transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “ligandable hotspots” that small-molecules can bind to modulate protein function. Our research group addresses this challenge by advancing and applying chemoproteomic platforms to discover and pharmacologically target unique and novel ligandable hotspots for disease therapy. We currently have three major research directions. Our first major focus is on developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel ligandable hotspots for undruggable protein targets and pathways. Our second research area focuses on using chemoproteomic platforms to expand the scope of targeted protein degradation technologies. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to develop new induced proximity-based therapeutic modalities. Collectively, our lab is focused on developing next-generation transformative medicines through pioneering innovative chemical technologies to overcome challenges in drug discovery.
Citation Format: Daniel K. Nomura. Reimagining druggability using chemoproteomic platforms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY17-03.
Abstract SY23-02: Elevated cellular stiffness sensitizes metastatic cells to destruction by mechanosurveillance: The mechanical mode of immune surveillance
Authors: Er Ekrem Emrah 
Published: June 2022

Abstract
Tumor evolution is coupled to profound biophysical changes in cancer cells and understanding how these changes impact metastasis can reveal novel therapeutic targets. One prominent biophysical characteristic of cancer cells is their stiffness. At the early steps of the metastatic cascade, transformed cells become physically softer and this allows them to invade into and to navigate through the surrounding extracellular matrix. Conversely, cancer cells that later intravasate into circulation need to maintain a higher degree of biophysical stiffness in order to withstand shear forces that otherwise cause mechanical rupture of cancer cells during hematogenous dissemination. However, the impact of cellular stiffness on the final stage of metastatic colonization in vital secondary organs is not well understood. We recently found that increasing stiffness of disseminated cancer cells sensitizes them to destruction by cytotoxic lymphocytes. Specifically, we found that myocardin related transcription factor (MRTFA/B) activity in cancer cells increases cancer cell stiffness, which then biophysically stimulates apoptotic cytokine production and cytolytic granule secretion in the adjoining CD8+ T- and Natural Killer (NK) cells for improved cytotoxicity. Our data highlighted the in vivo prevalence of the fundamental concepts in lymphocyte mechanobiology, which posit that increasing the stiffness of the surfaces that oppose T- and NK cells increases their cytolytic function through mechano-chemical signal transduction. We termed this mechanical mode of immune surveillance “mechanosurveillance” and showed that the expression of its molecular mediators cooperates with immune checkpoint blockade therapies in melanoma models and is associated with better patient survival in the clinic. In our current work, we utilized a series of novel biophysical approaches to measure the stiffness of metastatic foci in situ and to demonstrate that physically stiffer metastatic foci are eliminated by the immune surveillance. Furthermore, we used bioinformatics analyses of patient data and loss-of-function and gain-of-function experiments to identify therapeutically actionable proteins that increase cancer cell stiffness. Our findings revealed pharmacological manipulations that increase cancer cell stiffness and provided a road map for promoting mechanosurveillance in metastatic niches.
Citation Format: Ekrem Emrah Er. Elevated cellular stiffness sensitizes metastatic cells to destruction by mechanosurveillance: The mechanical mode of immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY23-02.
Abstract SY24-01: Changes in adaptive landscapes and somatic evolution as we age
Authors: DeGregori James V. 
Published: June 2022

Abstract
Why do we get cancer? Why is cancer highly associated with old age, and why are insults like smoking, obesity, and sunlight associated with increased risk of cancers? Of course, these contexts all cause mutations, and some of these mutations can contribute to malignant phenotypes. But we now understand that carcinogenesis is much more complex than originally appreciated. In particular, there are microenvironmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, somatic evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. We will discuss the evidence from many labs for microenvironmental change driven selection in the evolution of cancer, additional support from epidemiological and clinical studies, as well as the limitations, inconsistencies and unknowns that require the attention of cancer researchers. My own lab has been using mouse models of cancer initiation, mathematical models of clonal evolution, and analyses of human tissue samples to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. Using Monte Carlo modeling, we have explored the impact of key somatic evolutionary parameters on multi-stage carcinogenesis, revealing that two additional major mechanisms, aging-dependent somatic selection and life history-dependent evolution of species-specific tumor suppressor mechanisms, need to be incorporated into the multi-stage model of carcinogenesis to make it capable of generalizing cancer incidence across tissues and species. Using mouse models, we have shown that aging and inflammation dependent changes in tissue microenvironments dramatically impact the fitness impact of oncogenic mutations, leading to aging and inflammation driven clonal expansions in the hematopoietic compartment. These studies have also uncovered molecular mechanisms underlying oncogene-driven adaptation to aged and inflammatory tissue environments. In all, these studies indicate that strategies to prevent or treat cancers will need to incorporate interventions that alter tissue microenvironments. While we largely cannot prevent mutation accumulation through our lives, we do have the ability to manipulate tissue microenvironments so as to change the evolutionary trajectories of oncogenically-mutated cells.
Citation Format: James V. DeGregori. Changes in adaptive landscapes and somatic evolution as we age [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY24-01.
Abstract SY24-04: And by a sleep to say we end: Tumor dormancy, aging, and recurrent disease
Authors: Weeraratna Ashani T. 
Published: June 2022

Abstract
Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging. Our new data identify Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of soluble Wnt factors enabling efficient metastatic outgrowth. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung. Further these changes are also reflected in the response of tumor cells to therapy, linking dormancy to recurrent disease.
Citation Format: Ashani T. Weeraratna. And by a sleep to say we end: Tumor dormancy, aging, and recurrent disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY24-04.
Abstract SY30-01: Translational issues in lung cancer disparities: A vision for cancer equity
Authors: Hughes-Halbert Chanita 
Published: June 2022

Abstract
Lung cancer continues to be one of the leading causes of racial disparities in cancer morbidity and mortality among adults in the United States. Over the past 20 years, efforts to address disparities in lung cancer outcomes have focused on describing racial/ethnic differences in smoking behaviors and cessation outcomes. Other research has compared racial/ethnic groups in psychosocial and geographic risk factors for smoking and barriers to cessation; self-reported perceptions of stress and neighborhood deprivation have emerged as critical determinants of persistent tobacco use and predictors of relapse in disparity populations. Considerable investments have also been made to develop novel approaches for detecting lung cancer early and therapeutic strategies for treating this disease; lung cancer screening with LDCT now has a Grade B recommendation from the US Preventive Services Task Force and screening guidelines have been revised recently to be better aligned with the smoking behaviors and disease risk profiles among smokers from disparity populations. The demonstrated ability of LDCT to reduce lung cancer mortality is a significant clinical and public health advancement because it is the only evidence-based approach for detecting lung cancer at an early stage when treatment is most likely to be curative. However, several studies have demonstrated that patients from disparity populations have reduced uptake of cancer control strategies such as LDCT because of unmet social needs and risk factors; thus, revising lung cancer screening guidelines to be more inclusive may be necessary but not sufficient for improving access among disparity populations. The purpose of this presentation is to describe the goals and objectives for translational studies that are now being conducted to enhance equity in lung cancer outcomes among disparity populations and to identify priorities for future research in lung cancer equity.
Citation Format: Chanita Hughes-Halbert. Translational issues in lung cancer disparities: A vision for cancer equity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY30-01.
Abstract SY43-02: Adapting clinical radiation therapy to immune checkpoint blockade
Authors: Formenti Silvia C. 
Published: June 2022

Abstract
Focal radiation therapy has demonstrated to elicit inflammatory and immune responses that contribute to cancer immunosurveillance, but may also have unwanted systemic effects. The application of ionizing radiation to cancer, which is the basis for the field of radiation oncology, has evolved to define and exploit the therapeutic window between radiation cytocidal effects in tumors versus those in normal tissue. The original standardization of specific dose-fractionation regimens reflected the results of decades of empirical experience to find the best balance between local control of the irradiated cancer and the mitigation of risk for acute and late sequelae in the exposed normal tissues. More than a century of research in radiation biology has elucidated how radiation damage recruits a classical inflammation response, activates pathways to repair tissues through scavenging of cellular debris and canonical wound repair mechanisms that aim at recovering tissue integrity. Intrinsic to this process is a robust dampening of immunogenic signals, common to those associated with wound repair, to prevent triggering of auto-immune rejections of inflamed tissues. At the same time, radiation has proimmunogenic effects, that recruit both the innate arm of the immune system (acute induction of IFN pathways) and the adaptive arm, through radiation-induced neoepitopes and enhanced cross presentation. Strategies to uncouple these opposite effects are the focus of research efforts in multiple radiation biology laboratories, worldwide. The emergence of modern cancer immunotherapy offers the opportunity to further dissect such strategies. Recent evidence suggest a new role for focal radiotherapy, to partnering and synergize with immune checkpoint blockade (ICB). Evidence is emerging both preclinically and in the clinical setting that optimal integration of radiotherapy with the available immune modifiers might require changes in standard radiation oncology practices. Variables like the type of treatment fields, the inclusion of draining nodal stations, the degree of exposure of circulating immune cells, the type of dose-fractionation and the timing of radiotherapy during ICB all can affect the success of immunoradiotherapy combinations. Hence, defining the parameters for adapting classic radiation therapy to best integrate with ICB remains a fundamental area of investigation, as it is integral to a successful partnership with immunotherapy.
Citation Format: Silvia C. Formenti. Adapting clinical radiation therapy to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY43-02.
Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition
Authors: Alvarez-Breckenridge Christopher , Markson Samuel C. , Stocking Jackson H. , Nayyar Naema , Lastrapes Matt , Strickland Matthew R. , Kim Albert E. , de Sauvage Magali , Dahal Ashish , Larson Juliana M. , Mora Joana L. , Navia Andrew W. , Klein Robert H. , Kuter Benjamin M. , Gill Corey M. , Bertalan Mia , Shaw Brian , Kaplan Alexander , Subramanian Megha , Jain Aarushi , Kumar Swaminathan , Danish Husain , White Michael , Shahid Osmaan , Pauken Kristen E. , Miller Brian C. , Frederick Dennie T. , Hebert Christine , Shaw McKenzie , Martinez-Lage Maria , Frosch Matthew , Wang Nancy , Gerstner Elizabeth , Nahed Brian V. , Curry William T. , Carter Bob , Cahill Daniel P. , Boland Genevieve Marie , Izar Benjamin , Davies Michael A. , Sharpe Arlene H. , Suvà Mario L. , Sullivan Ryan J. , Brastianos Priscilla K. , Carter Scott L. 
Published: June 2022

Abstract

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.
Identification of Drug–Cancer Associations: A Nationwide Screening Study
Authors: Kristensen Kasper Bruun , Friis Søren , Lund Lars Christian , Hallas Jesper , Cardwell Chris R. , Andreassen Bettina K. , Habel Laurel A. , Pottegård Anton 
Published: June 2022

The main tool in drug safety monitoring, spontaneous reporting of adverse effects, is unlikely to detect delayed adverse drug effects including cancer. Hypothesis-free screening studies based on administrative data could improve ongoing drug safety monitoring. Using Danish health registries, we conducted a series of case–control studies by identifying individuals with incident cancer in Denmark from 2001 to 2018, matching each case with 10 population controls on age, sex, and calendar time. ORs were estimated using conditional logistic regression accounting for matching factors, educational level, and selected comorbidities. A total of 13,577 drug–cancer associations were examined for individual drugs and 8,996 for drug classes. We reviewed 274 drug–cancer pairs where an association with high use and a cumulative dose–response pattern was present. We classified 65 associations as not readily attributable to bias of which 20 were established as carcinogens by the International Agency for Research on Cancer and the remaining 45 associations may warrant further study. The screening program identified drugs with known carcinogenic effects and highlighted a number of drugs that were not established as carcinogens and warrant further study. The effect estimates in this study should be interpreted cautiously and will need confirmation targeted epidemiologic and translational studies.Significance:This study provides a screening tool for drug carcinogenicity aimed at hypothesis generation and explorative purposes. As such, the study may help to identify drugs with unknown carcinogenic effects and, ultimately, improve drug safety as part of the ongoing safety monitoring of drugs.
Environmental Law and Sustainable Tourism: critical analysis between environmental ethics and interests in relation to non-human animal life
Authors: Lopes Anderson Soares , Almeida Paulo Santos 
Published: June 2022

ABSTRACT This study aims to investigate the exploitation of animal life in tourism observed in certain tourist destinations, such as Jenipabu/RN, which uses dromedaries from the Canary Islands in ethical mismatch. As observed hypotheses, tourism as an economic activity does not share the parameters associated with the preservation of life and sustainability and the use of animals in tourism comes to constitute the reproduction of cases related to the exploitation and violation of animal rights, non-human lives. It is analyzed the evaluation of tourism development of a destination that uses nonhuman life in this activity in certain regions of Brazil. Through exploratory research and qualitative method, it investigates the bibliography, original documentation and articles that address sustainability parameters in Brazilian Environmental Law and tourism, through which it was diagnosed a sustainable development mean for the sector, since this activity tends to reach a factor of preservation of the fauna by contributing to conservation funds. As preliminary conclusion, it is stated that tourism planning needs to share guidelines to ensure the maintenance of animal life for inspection by the responsible agencies, particularly in organizations that use animals in their routine activities, and to encourage the creation and participation of multiple actors in courses of environmental education by promoting parameters of awareness of the maintenance and conservation of non-human life.Keywords: environmental law; sustainable tourism; environmental ethics; sustainability; non-human.
Efêmero Cênico - Eterna Continuidade no Trabalho Trabalho do Ator
Authors: Fortuna Marlene 
Published: June 2022

A arte do ator, diferente do que muitos supõem, não tem fim. Está atrelada ao Princípio de Continuidade, correspondendo assim à Semiótica de Charles Sanders Peirce. Seu percurso é um trilhar estético em constante mutação. Uma cadeia contínua que não termina, mesmo depois da estreia. A questão se difere com relação à atividade do dramaturgo, que, enquanto produtor de linguagem “fixa, passiva, inerte e surda”, tem seu texto pousado, horizontalmente, nas prateleiras das bibliotecas, sujeito a uma simples leitura até que seja (ou não) vitalizado pelos Poetas de Dioniso. A lida do Errante de Baco é vertical e já nasce morrendo. É efêmera, deslocável, seqüencial e líquida. Assim sendo, temos evanescência para o intérprete e durabilidade para o autor; imediatismo-mediatismo; instantaneidade-espera; presentidadeeternidade, respectivamente. Nenhum artista tem tão plena certeza de que suas operações de “manufatura” são trilhas de volatizações constantes como o ator, portador de um método artístico residido no inacabado. Ele sofre um confronto perturbável com o tempo, sem deixar lugar para o absoluto. Espetáculo pronto, não quer dizer findo, porque o que é cinético, o que é dinâmico e o que está na contemporaneidade de si mesmo, pela própria natureza, está sujeito a modificações permanentes. Ora, o mesmo personagem que energizado estava ontem em cena, hoje, já é outro, porque nós somos também outros a cada dia, em suporte perecível, como a vida. Por outro lado, não estamos nos referindo a fazer uma atuação a cada noite. Isto é caos e tende a enlouquecer o elenco, induzindo a montagem ao naufrágio. Propagamos a reiteração da mesma partitura, com recriações consecutivas. É ser capaz de tornar o “antigo conhecido” em “original desconhecido”. Um jogo! Uma estratégia! Um golpe de mestre! Se há engano certo naquele intérprete que julga ter chegado, na estreia, ao final de seu Processo de Criação, há engano também naquele que entende não precisar de tanto trabalho, de uma vez que sua atividade é fluida. Ao contrário, quanto mais liquidez, mais investimento em estudos, pesquisas de campo e bibliográficas, leituras, exercícios, formação requintada e exaustiva da aparelhagem técnica, da construção de um repertório que dê conta de tamanha volatilidade.