bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B009: Tumoral activation of endothelium drives macrophages-mediated metastatic niche formation and promotes lung metastasis
Authors: Chung Hyewon , Kim Sang Wha , Seok Seung Hyeok 
Published: January 2023

Abstract
Primary tumor induces macrophages-enriched environment to establish metastatic niche which enhances homing and colonization of circulating tumor cells. However, the molecular mechanism underlying endothelial remodeling that favors macrophages infiltration and subsequent niche formation is not fully understood. Here, we found that tumor-derived factors activated endothelial cells to increase adhesive efficacy of monocytes to the endothelium, leading to macrophage infiltration. In mouse models of pulmonary metastasis, this endothelial activation triggered formation of premetastatic niche via accumulation of macrophages in the lungs. Of note, macrophages primed the metastatic microenvironment through enhancing expression of niche-related genes including S100A8, S100A9, MMP9 and fibronectin within the premetastatic lungs and directly transmitted survival signal to tumor cells in a contact-dependent manner. Furthermore, we demonstrated that depletion of macrophages specifically during premetastatic stages reduced niche formation and also resulted in reduced metastatic burden. These findings suggest that endothelial remodeling at metastatic site is a key step for initiation of premetastatic niche formation supported by macrophages. Targeting this step could present an opportunity for therapeutic intervention of metastatic spread in patients with malignant cancers.
Citation Format: Hyewon Chung, Sang Wha Kim, Seung Hyeok Seok. Tumoral activation of endothelium drives macrophages-mediated metastatic niche formation and promotes lung metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B009.
Abstract IA001: Metastasis initiating cells and ecosystems
Authors: Massagué Joan 
Published: January 2023

Abstract
Metastasis is initiated and sustained through therapy by cancer cells with stem-like properties, termed metastasis initiating cells (MICs). Recent work suggests that MICs are malignant cells that adopted a regenerative stem-cell phenotype with intrinsic programs to survive the physical, immune and metabolic stresses of the metastatic process, enter a slow-cycling state for dormancy, and establish supportive interactions with organ-specific ecosystems for eventual outgrowth and recurrence. Notably, relapse frequently develops from disseminated MICs that remain dormant in distant organs after the apparently successful treatment of a primary tumor. During dormancy, MICs fluctuate between immune evasive quiescent and cell cycle reentry states, which exposes them to elimination by the immune system. By combining novel immunocompetent mouse models of lung adenocarcinoma indolent metastasis, in vivo genetic screens, immune profiling, and pre-clinical anti-tumor drug testing, we identified specific pathways in reawakened MICs that drive immune-mediated clearance and can be therapeutically activated to hasten the elimination of residual disseminated disease. Moreover, analysis of brain metastasis with advanced imaging reveals that the interplay between MICs and their host ecosystem is influenced by the architecture of metastatic colonies. Thus, lung adenocarcinoma and triple-negative breast cancer metastases grow by spreading on the basement membrane of brain capillaries, forming perivascular tumor colonies that closely interact with microglia and astrocytes. In contrast, HER2+ breast cancer cells adopt a spheroidal growth pattern that is driven by tumor-derived extracellular matrix and restricts microglia and astrocyte infiltration. The use of single-cell analytics revealed distinct microglia activation states, MIC dependencies and vulnerabilities associated with these different growth patterns. This progress sheds light on the complex and dynamic interplay between MICs and their host ecosystems and point at therapeutically actionable targets to hasten the elimination of disseminated disease.
Citation Format: Joan Massagué. Metastasis initiating cells and ecosystems [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA001.
Abstract IA006: EMT-induced tumor plasticity in cancer metastasis
Authors: Mani Sendurai A 
Published: January 2023

Abstract
Advancements in diagnosis and treatment help save cancer patients if the patient presents with local disease. However, the survival probability drops significantly when the tumor metastasizes to other organs. Cancer stem cells (CSCs) are responsible for developing resistance to chemotherapy, tumor relapse, and metastasis. We and others found that the latent embryonic program epithelial to mesenchymal transition (EMT), known to induce mesenchymal properties, including increased migration and invasion, can also induce stem cell properties in cancer cells. This finding postulates that the tumor is inherently capable of generating CSCs de novo and promoting plasticity and heterogeneity. Using syngeneic orthotopic tumor models, we found that CD8+ T cells play a vital role in regulating metastasis besides plasticity in tumor cells. This finding suggests that targeting EMT-signaling pathways and immune cells may provide a window of opportunity to treat metastasis, chemoresistance, and tumor relapse.
Citation Format: Sendurai A Mani. EMT-induced tumor plasticity in cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA006.
Abstract IA007: Regulation of metastasis efficiency via mitochondrial genetics
Authors: Welch Danny R. 
Published: January 2023

Abstract
While there has been increasing appreciation for the roles of mitochondria in cancer, most efforts investigating the genetics of cellular functions study only the nuclear genome. To overcome technical complications of studying the specific contributions of mitochondrial genetics, we created mitochondrial nuclear exchange (MNX) mice by transferring an oocyte nucleus from strain-x into an enucleated oocyte from strain-y. Using MNX mice, we made the following discoveries demonstrating the profound role(s) of mtDNA on several complex phenotypes. - Crossing nuclear genome-matched female mice with male transgenic mice bearing oncogenes, tumorigenicity and metastasis were up- or down-regulated depending upon mtDNA. - MNX mice exhibit different autochthonous tumor formation. - When syngeneic (i.e., histocompatible) mammary and melanoma cells were injected into MNX mice, metastasis changed 3-5X, depending on mtDNA SNP. C57BL/6J mtDNA inhibited metastasis while C3H/HeN mtDNA increased metastasis. - MNX mice have selectively altered epigenetic marks (DNA methylation and histone marks) in the nuclear genome. - MNX mice with higher ROS form more metastases. Scavenging ROS reduced metastasis. - Baseline immune profiles differ in MNX mice compared to nDNA-matched counterparts and polarization states of myeloid populations infiltrating lung metastases were also significantly different. - Metabolomic profiling of &gt;5000 metabolites showed minor differences, none of which appear to correlate with the above-referenced phenotypic changes. - MNX mice have distinct gut microbiota than matched wild-type strains, suggesting mitochondrial-bacterial communication. Together, these results demonstrate that mitochondrial genes are among metastatic quantitative trait loci by intrinsic and extrinsic mechanisms. Candidate signals from mitochondria to the nucleus or bacteria will be reported. And since mitochondrial SNP are markers of genetic ancestry, our findings also suggest that mtDNA SNP could serve as prognostic biomarkers and partially explain racial disparities in disease severity. Support: Susan G. Komen for the Cure (SAC11037), METAvivor Research & Support Inc., National Foundation for Cancer Research, National Cancer Institute P30-CA168524.
Citation Format: Danny R. Welch. Regulation of metastasis efficiency via mitochondrial genetics [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA007.
Abstract IA017: The elusive ‘metastasis driver’: Is it hiding in plain sight
Authors: Stanger Ben 
Published: January 2023

Abstract
Recurrent single nucleotide mutations are a common feature of primary tumor evolution, where mutations in genes such as KRAS, APC, TP53, and BRAF are important drivers of malignancy. Efforts to identify comparable mutations that are exclusive to metastatic lesions - so-called 'metastasis drivers' - have been harder to find. However, the search for such metastasis-enabling genetic events has largely been limited to single nucleotide variants rather than chromosomal alterations (copy number gains and losses), which are far more common in advanced tumors. In this study, we used a stochastic mouse model of pancreatic cancer which gives rise to both highly metastatic and poorly metastatic tumors to interrogate the molecular correlates of metastatic heterogeneity. Our analysis revealed that focal amplifications of the MYC oncogene, but not other oncogenic drivers, were associated with the highly metastatic phenotype. Moreover, highly metastatic tumors exhibited elevated levels of MYC protein and greater expression of MYC target genes. This relationship between MYC copy number and metastasis was also observed in human samples, where MYC amplifications were found in 11% of metastases but fewer than 2% of primary tumors. Mechanistically, MYC enhances metastasis by recruiting pro-invasive macrophages, leading to greater vascular intravasation of tumor cells. These results nominate MYC as a bona fide metastasis driver gene and highlight the importance of considering copy number alterations in the evaluation of genetic mediators of metastasis.
Citation Format: Ben Stanger. The elusive ‘metastasis driver’: Is it hiding in plain sight [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA017.
Abstract IA019: Unique features and dependencies of brain metastases
Authors: Davies Michael A. 
Published: January 2023

Abstract
Metastasis to the central nervous system (CNS), including the brain and leptomeninges, is one of the most common and devastating complications of metastatic melanoma. Metastasis to the brain is detected in 40-60% of stage IV melanoma patients. CNS metastasis remains a leading cause of morbidity and mortality from this disease, and a common site of therapeutic resistance. Improving outcomes in these patients is made challenging by the relatively limited understanding of the features of these tumors- and exacerbated by the frequent exclusion of patients with brain metastases from clinical trials. There is growing evidence that brain metastases from melanoma and other cancers harbor/share unique features that drive the aggressive nature and therapeutic resistance of these tumors. Studies across cancer types have revealed differences in the immune microenvironment of the tumors, as well as their oncogenic mutations and activation of key signaling pathways. Recently, multiple laboratories have identified unique metabolic features of these tumors. Several of these studies have identified novel metabolic dependencies of brain metastases- and suggest a novel paradigm of therapeutic agents (and clinical trials) that are expected to achieve greater benefit in patients with CNS involvement than without. Such findings are leading to the development of both clinics and clinical trials focused on brain metastases across cancer types. They are also leading to further investigations to determine the role of these features in the initiation, progression, and resistance of brain metastases.
Citation Format: Michael A. Davies. Unique features and dependencies of brain metastases [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA019.
Abstract PR003: OXPHOS impairing mitochondrial DNA mutations suppress melanoma growth and metastatic progression
Authors: Shelton Spencer , House Sara , Ramesh Vijayashree , Chen Zhengkang , Llamas Claire , Tasdogan Alpaslan , DeBerardinis Ralph , Morrison Sean , Mishra Prashant 
Published: January 2023

Abstract
Cancers acquire somatic mitochondrial DNA (mtDNA) mutations undetected in surrounding tissues. Cancer-specific mtDNA mutations primarily constitute variants of unknown significance whose oncogenic consequences are poorly understood. Analysis of large-scale sequencing datasets suggests that human cancers generally select against severe mtDNA mutations; however, the presence of selective pressure on the mtDNA genome has yet to be experimentally demonstrated. Here we optimized a FACS-based protocol to reconstitute the highly metastatic human melanoma cell line A375 with exogenous mtDNA, thereby generating nuclear-isogenic cytoplasmic hybrid (cybrid) lines. Homoplasmic cybrids were generated exclusively harboring either exogenous wildtype mtDNA, mtDNA with partial loss of OXHPHOS function (SNPs in mt.ND1 (of Complex I) or mt.ATP6 (of Complex V)), or mtDNA with complete loss of OXPHOS function (derived from a human melanoma harboring a truncating frameshift mutation in mt.CO1 (of Complex IV)). Compared to wildtype cybrids, subcutaneous xenografts of ND1 and ATP6 cybrids into NOD–SCID Il2rg−/− (NSG) mice had elevated primary tumor ROS levels and similar primary tumor growth rates. Xenografts of our most dysfunctional OXPHOS cybrid, CO1, formed tumors albeit with lowered growth rates. Uniquely, the ND1 and CO1 xenografts respectively exhibited diminished metastatic burden and no metastatic burden. Our results suggest that OXPHOS impairing mtDNA mutations are tolerable during primary tumor growth but reduce the severity and incidence of metastasis. Lastly, we generated heteroplasmic A375 cybrids, harboring both wild-type and mutant alleles, and developed a ddPCR method to characterize allelic frequency with single-cell precision. Extended in vitro passage of the heteroplasmic cybrids failed to significantly shift the heteroplasmic mtDNA allelic frequency. However, following subcutaneous xenografting of the heteroplasmic cybrids, primary tumors significantly shifted their variant allele frequency to favor the wildtype allele. In summary, these results indicate that a functional mtDNA haplotype is not absolutely required for tumorigenesis but contributes to metastatic efficiency. In addition, we experimentally demonstrated the existence of selective pressure in favor of functional mtDNA during tumorigenesis.
Citation Format: Spencer Shelton, Sara House, Vijayashree Ramesh, Zhengkang Chen, Claire Llamas, Alpaslan Tasdogan, Ralph DeBerardinis, Sean Morrison, Prashant Mishra. OXPHOS impairing mitochondrial DNA mutations suppress melanoma growth and metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR003.
Abstract PR010: Multiplex imaging reveals features of organotropism in pancreatic ductal adenocarcinoma
Authors: Eng Jennifer , Link Jason , Pelz Carl , Sears Rosalie 
Published: January 2023

Abstract
PDAC patients have a dismal prognosis with an 11% 5-year survival rate, driven in part by the fact that 90% of patients are diagnosed with metastatic disease. In a cohort of 300 PDAC patients, we observed that patients who had lung-only metastasis had longer overall survival than the majority of patients with metastasis to the liver. We used gene expression data to develop a signature based on gene expression in primary tumors of liver versus lung organotropism, which we called pORG. Our pORG signature predicts long term survival in PDAC patients and reveals unique features of the primary tumor, including increased interferon and immune activity in lung tropic tumors and increased proliferation and replication stress in liver-tropic tumors. To validate our findings, we generated cyclic immunofluorescence multiplex imaging data for a subset of 34 patients. Single cell image analysis revealed B and T cell infiltration and spatial clustering in low pORG/ lung tropic tumors, and markers of replication stress in high pORG patients. Our work suggests unique targetable tumor and microenvironment features linked to organotropism in PDAC.
Citation Format: Jennifer Eng, Jason Link, Carl Pelz, Rosalie Sears. Multiplex imaging reveals features of organotropism in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR010.
Geoparques: desenvolvimento sustentável e agenda 2030
Authors: Fleig Raquel , Nascimento Iramar Baptiptistella do , Valdati Jairo 
Published: January 2023

Geoparque é um território reconhecido pela UNESCO pelo seu patrimônio abiótico onde se aplicam estratégias de desenvolvimento sustentável, atenta ser uma estratégia para o alcance da sustentabilidade global e uma maneira sociocultural particular de uma população de compreender o contexto da natureza local. A pesquisa teve como objetivo principal identificar como os geoparques podem cumprir a agenda 2030, e como objetivos específicos conhecer quais geoparques já existem, que propósitos atendem e quais estão em avaliação no Brasil, revisar os termos pertinentes à criação de geoparques e os desafios de sua implantação. O estudo bibliográfico ocorreu por meio de uma revisão integrativa nas bases de dados da CAPES: Web of Science e Scopus, em livros, e em alguns sites oficiais de organizações de geoparques. Existem 177 geoparques chancelados pela UNESCO no mundo, e alguns projetos no aguardo de avaliação. No Brasil, o Geopark Araripe, o Seridó e o Geoparque Caminhos dos Cânions do Sul são chancelados pela UNESCO. As diretrizes para o desenvolvimento sustentável nos geoparques envolvem uma concepção multidisciplinar de ações educativas, geoturísticas e geoconservadoras que impulsionam o desenvolvimento sócio econômico local, uma vez que sobrepõe a necessidade de interpretação sobre os elementos abióticos instituídos nas instruções da biodiversidade. O conhecimento sobre os geoparques já existentes no mundo e sua distribuição territorial permitiram identificar o movimento que os países têm feito a favor do desenvolvimento sustentável e para atender a Agenda 2030.
The Church Sinister
Authors: Harmes Marcus , Harmes Meredith , Harmes Barbara 
Published: January 2023

Abstract
The exorcism of Michael Taylor in 1974, which led to murder, pushed Anglican exorcisms into the public gaze. This article proposes a particular trajectory of Anglicanism and the preternatural into popular culture and popular awareness of religion. The Taylor case was one of the catalysts for private anxiety among clergy about the preternatural in the Church of England. By the early 1970s, some clergy ignited public debate including open letters and television appearances to declare the Church of England should not exorcise and complete belief in the accounts of the Gospels was not necessary. Their debate moved to television, some clergy declaring on talk shows the Church should not exorcise, others consenting to be filmed exorcising. Clergy exorcising on screen gave visual cues and content to fictional drama that traversed different genres and channels. This article identifies a common element to drama showcasing the Church and the preternatural, showing the institution and its clergy as weak or absent in the face of evil. Drama brought to the fore clerical concerns that engaging publicly with the preternatural made the Church seem theologically confused and denuded of spiritual authority, a point reinforced by the tragic real-world consequences of the Anglican exorcism of Michael Taylor.
Vascular “Long COVID”: A New Vessel Disease?
Authors: Zanini Giada , Selleri Valentina , Roncati Luca , Coppi Francesca , Nasi Milena , Farinetti Alberto , Manenti Antonio , Pinti Marcello , Mattioli Anna Vittoria 
Published: January 2023

Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as “Long Covid (LC)” disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first “endotheliitis,” is often followed by production of “Neutrophil Extracellular Trap,” and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible “LC” disease.
The Help-Seeking Experiences of Family and Friends Who Support Young People With Mental Health Issues: A Qualitative Study
Authors: Migliorini Christine , Barrington Nicholas , O’Hanlon Brendan , O’Loughlin Gretel , Harvey Carol 
Published: January 2023

Little has been documented of the journey that family and friends (F&F) undertake when supporting a young person aged 12–25 years struggling with mental illness. The experiences of family and friends were explored using an online qualitative survey ( N = 58) and semi-structured interviews ( n = 15). Recruitment was through a national youth mental health service Facebook page and website. An experiential thematic analysis was conducted focusing on participants’ experiences and sense of their world. Strong feelings and challenging life circumstances made the context of help-seeking complicated. Despite following usual avenues for advice or support, F&F still came across professionals and a health/mental health system that compounded their distress. It was the simpler things that some professionals did that made their journey more bearable. Useful insights derived from the narratives allow service improvement recommendations such as reminding professionals of the multiplicity of stressors commonplace to families and the value of validation and acknowledgement.