Activation of Oncogenic and Immune-Response Pathways Is Linked to Disease-Specific Survival in Merkel Cell Carcinoma

Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin with a poor prognosis. Improving the prognosis of MCC by means of targeted therapies requires further understanding of the mechanisms that drive tumor progression. In this study, we aimed to identify the genes, processes, and pathways that play the most crucial roles in determining MCC outcomes. Methods: We investigated transcriptomes generated by RNA sequencing of formalin-fixed paraffin-embedded tissue samples of 102 MCC patients and identified the genes that were upregulated among survivors and in patients who died from MCC. We subsequently cross-referenced these genes with online databases to investigate the functions and pathways they represent. We further investigated differential gene expression based on viral status in patients who died from MCC. Results: We found several novel genes associated with MCC-specific survival. Genes upregulated in patients who died from MCC were most notably associated with angiogenesis and the PI3K-Akt and MAPK pathways; their expression predominantly had no association with viral status in patients who died from MCC. Genes upregulated among survivors were largely associated with antigen presentation and immune response. Conclusion: This outcome-based discrepancy in gene expression suggests that these pathways and processes likely play crucial roles in determining MCC outcomes.Peer reviewe

Activation of Oncogenic and Immune-Response Pathways Is Linked to Disease-Specific Survival in Merkel Cell Carcinoma

Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin with a poor prognosis. Improving the prognosis of MCC by means of targeted therapies requires further understanding of the mechanisms that drive tumor progression. In this study, we aimed to identify the genes, processes, and pathways that play the most crucial roles in determining MCC outcomes. Methods: We investigated transcriptomes generated by RNA sequencing of formalin-fixed paraffin-embedded tissue samples of 102 MCC patients and identified the genes that were upregulated among survivors and in patients who died from MCC. We subsequently cross-referenced these genes with online databases to investigate the functions and pathways they represent. We further investigated differential gene expression based on viral status in patients who died from MCC. Results: We found several novel genes associated with MCC-specific survival. Genes upregulated in patients who died from MCC were most notably associated with angiogenesis and the PI3K-Akt and MAPK pathways; their expression predominantly had no association with viral status in patients who died from MCC. Genes upregulated among survivors were largely associated with antigen presentation and immune response. Conclusion: This outcome-based discrepancy in gene expression suggests that these pathways and processes likely play crucial roles in determining MCC outcomes.Peer reviewe

LRIG1 is a positive prognostic marker in Merkel cell carcinoma and Merkel cell carcinoma expresses epithelial stem cell markers

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine malignancy of the skin. The cell of origin of MCC is thus far unknown and proposed cells of origin include Merkel cells, pro-/pre- or pre-B cells, epithelial stem cells, and dermal stem cells. In this study, we aimed to shed further light on the possibility that a subset of MCC tumors arise from epithelial stem cells of the skin by examining the expression of hair follicle and epidermal stem cell markers in MCC and normal human skin. We also aimed to elucidate any correlation between the expression of these markers and tumor Merkel cell polyomavirus (MCPyV) status or other clinicopathological characteristics or patient survival. Expression of CK19, SOX9, LGR5, and LRIG1 in MCC and normal human skin was studied by immunohistochemistry, and the staining patterns or intensities were statistically correlated with patient, tumor, MCPyV, and survival parameters. In a cohort of 137 cases of MCC, we observed dot-like immunoexpression of CK19 in 30 cases (22.1%) and homogeneous expression in 103 cases (75.7%). We also observed positive immunoexpression of SOX9 in 21 cases (15.3%), LGR5 in 118 cases (86.1%), and LRIG1 in 117 cases (86.0%). Immunoexpression of LRIG1 was found to correlate with better overall and MCC-specific survival. We observed frequent immunoexpression of several hair follicle and epidermal stem cell markers in MCC and found LRIG1 to be a positive prognostic marker in MCC.Peer reviewe

Exploring and contextualizing public opposition to renewable electricity in the United States

This article explores public opposition to renewable power technologies in the United States. It begins by discussing the genesis of environmental ethics, or how some Americans have come to place importance on the protection of the environment and preservation of species, ecosystems, and the biosphere. As result, renewable power systems have become challenged on ethical and environmental grounds and are occasionally opposed by local communities and environmentalists. The article finds that, however, such concern may be misplaced. Renewable electricity resources have many environmental benefits compared to power stations fueled by coal, oil, natural gas, and uranium. Opposition towards renewable resources can at times obscure the true costs and risks associated with electricity use and entrench potential racial and class-based inequalities within the current energy system

The 44Ti-powered spectrum of SN 1987A

SN 1987A provides a unique opportunity to study the evolution of a supernova from explosion into very late phases. Due to the rich chemical structure, the multitude of physical process involved, and extensive radiative transfer effects, detailed modeling is needed to interpret the emission from this and other supernovae. In this paper, we analyze the late-time (~8 years) HST spectrum of the SN 1987A ejecta, where 44Ti is the dominant power source. Based on an explosion model for a 19 Msun progenitor, we compute a model spectrum by calculating the degradation of positrons and gamma-rays from the radioactive decays, solving the equations governing temperature, ionization balance and NLTE level populations, and treating the radiative transfer with a Monte Carlo technique. We obtain a UV/optical/NIR model spectrum which is found to reproduce most of the lines in the observed spectrum to good accuracy. We find non-local radiative transfer in atomic lines to be an important process also at this late stage of the supernova, with ~30% of the emergent flux in the optical and NIR coming from scattering/fluorescence. We investigate the question of where the positrons deposit their energy, and favor the scenario where they are locally trapped in the Fe/He clumps by a magnetic field. Energy deposition into these largely neutral Fe/He clumps makes Fe I lines prominent in the emergent spectrum. Using the best available estimates for the dust extinction, we determine the amount of 44Ti produced in the explosion to 1.5\pm0.5 * 10^-4 Msun.Comment: 23 pages, 9 figures. 44Ti mass updated from 1.4E-4 to 1.5E-4 Msu

Phylogenetic Distinctiveness of Middle Eastern and Southeast Asian Village Dog Y Chromosomes Illuminates Dog Origins

Modern genetic samples are commonly used to trace dog origins, which entails untested assumptions that village dogs reflect indigenous ancestry or that breed origins can be reliably traced to particular regions. We used high-resolution Y chromosome markers (SNP and STR) and mitochondrial DNA to analyze 495 village dogs/dingoes from the Middle East and Southeast Asia, along with 138 dogs from >35 modern breeds to 1) assess genetic divergence between Middle Eastern and Southeast Asian village dogs and their phylogenetic affinities to Australian dingoes and gray wolves (Canis lupus) and 2) compare the genetic affinities of modern breeds to regional indigenous village dog populations. The Y chromosome markers indicated that village dogs in the two regions corresponded to reciprocally monophyletic clades, reflecting several to many thousand years divergence, predating the Neolithic ages, and indicating long-indigenous roots to those regions. As expected, breeds of the Middle East and East Asia clustered within the respective regional village dog clade. Australian dingoes also clustered in the Southeast Asian clade. However, the European and American breeds clustered almost entirely within the Southeast Asian clade, even sharing many haplotypes, suggesting a substantial and recent influence of East Asian dogs in the creation of European breeds. Comparison to 818 published breed dog Y STR haplotypes confirmed this conclusion and indicated that some African breeds reflect another distinct patrilineal origin. The lower-resolution mtDNA marker consistently supported Y-chromosome results. Both marker types confirmed previous findings of higher genetic diversity in dogs from Southeast Asia than the Middle East. Our findings demonstrate the importance of village dogs as windows into the past and provide a reference against which ancient DNA can be used to further elucidate origins and spread of the domestic dog

Sociotechnical agendas: reviewing future directions for energy and climate research

The field of science and technology studies (STS) has introduced and developed a “sociotechnical” perspective that has been taken up by many disciplines and areas of inquiry. The aims and objectives of this study are threefold: to interrogate which sociotechnical concepts or tools from STS are useful at better understanding energy-related social science, to reflect on prominent themes and topics within those approaches, and to identify current research gaps and directions for the future. To do so, the study builds on a companion project, a systematic analysis of 262 articles published from 2009 to mid-2019 that categorized and reviewed sociotechnical perspectives in energy social science. It identifies future research directions by employing the method of “co-creation” based on the reflections of sixteen prominent researchers in the field in late 2019 and early 2020. Drawing from this co-created synthesis, this study first identifies three main areas of sociotechnical perspectives in energy research (sociotechnical systems, policy, and expertise and publics) with 15 topics and 39 subareas. The study then identifies five main themes for the future development of sociotechnical perspectives in energy research: conditions of systematic change; embedded agency; justice, power, identity and politics; imaginaries and discourses; and public engagement and governance. It also points to the recognized need for pluralism and parallax: for research to show greater attention to demographic and geographical diversity; to stronger research designs; to greater theoretical triangulation; and to more transdisciplinary approaches

Clues to Cellular Ancestry and Novel Biomarkers in Merkel Cell Carcinoma

Background and purpose: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin with an unknown cell of origin. The oncogenic Merkel cell polyomavirus (MCPyV) is integrated in the tumor cell genome in most MCC tumors. Suspected cells of origin include epithelial stem cells of the epidermis, dermal stem cells, and pro/pre- or pre-B-cells. MCC is also suspected to have more than one cell of origin and represent more than one type of carcinoma which should perhaps be treated differently clinically. The unknown cell of origin hinders the development of animal models, hampering the testing of novel pharmacological therapy options. MCC has a poor prognosis and there are limited therapy options for metastatic MCC. There are currently no standardized prognostic markers, nor biomarkers guiding the choice of therapy, in widespread clinical use. We aimed to identify potential prognostic markers, markers for guiding therapy selection, and targets for precision therapy in MCC. We further aimed to gain insights concerning the cellular ancestry of MCC, expecially concerning the multiple cell of origin hypothesis. Methods: Studies I and II investigated the immunohistochemical expression of the B-lymphoid lineage markers PAX5 and TdT and the epithelial stem cell markers CK19, LRIG1, LGR5, and SOX9 and statistically correlated the expression patterns with clinicopathological parameters. Study III investigated the differential gene expression between tumors of survivors and tumors of patients who died from MCC. The differentially expressed genes were cross-referenced with the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes databases. We also conducted a manual literature review of the differentially expressed genes. In study IV, we performed a hierarchical clustering analysis of MCC tumors based on their expression patterns of the top 200 genes expressed with the widest variability. Clinicopathological parameters were statistically compared between the three molecular MCC subtypes identified in this clustering analysis. The three gene clusters exhibiting the greatest expression differences between these subtypes were cross-referenced with the GO database. Results: Immunohistochemical analyses revealed frequent expression of both B-lymphoid lineage markers and epithelial stem cell markers in MCC. LRIG1 was found to be a positive prognostic marker. Differential gene expression analyses identified 50 genes upregulated in tumors of patients who died from MCC and 29 genes upregulated in tumors of survivors. The genes upregulated in tumors of patients who died from MCC were associated with oncogenic pathways and processes such as angiogenesis and the PI3K-Akt and MAPK signaling pathways while the genes upregulated in tumors of survivors were largely associated with immune response. The hierarchical clustering analysis revealed three distinct molecular MCC subtypes with differing prognoses. One subtype consisted primarily of MCPyV-negative tumors and exhibited higher expression of embryonic genes and lower expression of neuroendocrine genes relative to the two other, primarily MCPyV-positive subtypes. The MCPyV-negative subtype and one of the two MCPyV-positive subtypes exhibited higher expression of genes related to epidermal structrures and processes and were more frequently located in a sun-exposed location relative to the other MCPyV-positive subtype. Conclusions: We observed findings consistent with MCC having more than one cell of origin. The dichotomous expression of genes related to epidermal structures and processes and the more frequent sun-exposed localization of tumors with high expression of these genes would be consistent with MCC having both an epidermal and a deeper, non-epidermal origin. Transcriptomic analyses revealed outcome-based differential expression of numerous genes associated with therapeutically targetable biological processes and signaling pathways in MCC, indicating that these genes, processes, and pathways play key roles in determining MCC outcome. Further studies are required to determine if some of these genes, processes, and pathways can be used as biomarkers for prognostic evaluation or therapy selection or can be targeted in the treatment of MCC.Merkelcellskarcinom (MCC) är en aggressiv typ av hudcancer som härstammar från en okänd ursprungscell. Det onkogena Merkelcellpolyomaviruset (MCPyV) är integrerat i tumörcellsgenomet i ca. 80% av MCC tumörer. Bland de misstänkta ursprungscellerna finns bl.a. epiteliala stamceller i epidermis, dermala stamceller och pro/pre- eller pre-B-celler. MCC misstänks även ha flera än en ursprungscell och således representera flera än en typ av karcinom som grupperas samman p.g.a. fenotyplikheter men möjligen borde behandlas olikt kliniskt. Den okända ursprungscellen försvårar utvecklingen av djurmodeller och således in vivo-studier av potentiella nya läkemedel. Prognosen för MCC är dålig och terapialternativen för metastaserad MCC är begränsade. Det finns tills vidare inga standardiserade prognostiska markörer eller markörer för att vägläda terapival i utbrett kliniskt bruk. Målen med detta avhandlingsprojekt var att nå nya insikter gällande det cellulära ursprunget av MCC, speciellt gällande teorin om flera ursprungsceller, samt att identifiera potentiella progostiska markörer, mål för precisionsmedicin samt markörer som kan vägleda terapival i MCC. I dessa syften undersökte vi expressionen av epiteliala stamcellsmarkörer och B-cellsmarkörer i MCC och utförde en hierarkisk klusteranalys baserad på expressionen av de gener som uttrycks med störst varians mellan olika MCC tumörer. Vi undersökte även genexpressionsskillnaderna mellan tumörer från patienter som dog av MCC och patienter som överlevde. MCC uppvisade frekvent expression av såväl epiteliala stamcellsmarkörer som B-cellsmarkörer och den epiteliala stamcellsmarkören LRIG1 visade sig vara en positiv prognostisk markör. Tumörer från patienter som dog av MCC uppvisade högre expression av gener som fungerar i olika onkogena processer och signalvägar såsom angiogenes och PI3K-Akt och MAPK signalvägarna medan tumörer från patienter som överlevde uppvisade högre expression av gener associerade med immunförsvar. Vidare undersökningar fordras för att avgöra om vissa av dessa gener och signalvägar kan användas som prognostiska markörer, kan användas för att vägleda terapival eller kan angripas farmakologiskt i vården av MCC. Den hierarkiska klusteranalysen identifierade tre molykylära undertyper av MCC med olika prognos: en huvudsakligen MCPyV-negativ och två huvudsakligen MCPyV-positiva undertyper. Den MCPyV-negativa och den ena MCPyV-positiva undertypen uppvisade högre expression av gener associerade med epidermala strukturer och processer och var oftare belägna på solexponerade områden än den andra MCPyV-positiva undertypen, detta kan implicera att MCC har såväl ett epidermalt som ett icke-epidermalt ursprung

Transcriptomic Analyses Reveal Three Distinct Molecular Subgroups of Merkel Cell Carcinoma with Differing Prognoses

Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine malignancy with a poor prognosis and an unknown cell of origin. Proffered cells of origin include epithelial stem cells of the hair follicle or interfollicular epidermis, dermal stem cells and pro/pre- or pre-B cells. MCC has also been proposed to have more than one cell of origin and indeed to represent more than one type of carcinoma, currently grouped together due to phenotypic similarities. We explored the heterogeneous nature of MCC by studying the most variably expressed genes with the goal of identifying gene expression patterns that are either clinically relevant or have implications regarding the cell(s) of origin. We performed RNA sequencing on primary tumor samples from 102 patients and identified the top 200 most variably expressed genes. These genes and the tumor samples were hierarchically clustered based on their expression. The functions of three gene clusters exhibiting clearly divergent expression between samples were studied by cross-referencing the lists of genes with online databases. High expression of a gene cluster related to embryonic developmental processes and low expression of a gene cluster related to neuroendocrine processes distinguished Merkel cell polyomavirus (MCPyV)-negative tumors from MCPyV-positive tumors. Furthermore, two prognostically relevant subgroups of MCPyV-positive MCC were identified based on dichotomic expression of genes related to epidermal structures and processes. We identified three distinct molecular subgroups of MCC with prognostic relevance. We propose that the dichotomic expression of epidermis-related genes might reflect both an epidermal and a nonepidermal origin for MCPyV-positive MCC.Peer reviewe