bluuebunny/crossref_metadata_2025_split huggingface dataset:
Everolimus Inhibits the Progression of Ductal Carcinoma In Situ to Invasive Breast Cancer Via Downregulation of MMP9 Expression
Authors: Chen Guang , Ding Xiao-Fei , Pressley Kyle , Bouamar Hakim , Wang Bingzhi , Zheng Guixi , Broome Larry E. , Nazarullah Alia , Brenner Andrew J. , Kaklamani Virginia , Jatoi Ismail , Sun Lu-Zhe 
Published: December 2019

Abstract

Purpose:
We evaluated the role of everolimus in the prevention of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) progression.

Experimental Design:
The effects of everolimus on breast cancer cell invasion, DCIS formation, and DCIS progression to IDC were investigated in a 3D cell culturing model, intraductal DCIS xenograft model, and spontaneous MMTV-Her2/neu mouse model. The effect of everolimus on matrix metalloproteinase 9 (MMP9) expression was determined with Western blotting and IHC in these models and in patients with DCIS before and after a window trial with rapamycin. Whether MMP9 mediates the inhibition of DCIS progression to IDC by everolimus was investigated with knockdown or overexpression of MMP9 in breast cancer cells.

Results:
Everolimus significantly inhibited the invasion of human breast cancer cells in vitro. Daily intragastric treatment with everolimus for 7 days significantly reduced the number of invasive lesions from intraductal DCIS foci and inhibited DCIS progression to IDC in the MMTV-Her2/neu mouse mammary tumor model. Mechanistically, everolimus treatment decreased the expression of MMP9 in the in vitro and in vivo models, and in breast tissues from patients with DCIS treated with rapamycin for 1 week. Moreover, overexpression of MMP9 stimulated the invasion, whereas knockdown of MMP9 inhibited the invasion of breast cancer cell–formed spheroids in vitro and DCIS in vivo. Knockdown of MMP9 also nullified the invasion inhibition by everolimus in vitro and in vivo.

Conclusions:
Targeting mTORC1 can inhibit DCIS progression to IDC via MMP9 and may be a potential strategy for DCIS or early-stage IDC therapy.
Phosphodiesterase 3A Represents a Therapeutic Target that Drives Stem Cell–like Property and Metastasis in Breast Cancer
Authors: Hao Na , Shen Wenzhi , Du Renle , Jiang Shan , Zhu Junyong , Chen Yanan , Huang Chongbiao , Shi Yi , Xiang Rong , Luo Yunping 
Published: December 2019

Abstract
Considerable evidence suggests that as breast cancer progresses, genetic and epigenetic mechanisms contribute to the emergence of self-renewing cells (CSC), which may also arise as a consequence of metastasis. Although the molecular pathways that trigger stemness and metastasis are known, key molecular and mechanistic gaps in our understanding of these processes remain unclear. Here, we first screened the inflammation-associated stemness gene phosphodiesterase 3A (PDE3A) using a medium-throughput siRNA library, which was overexpressed in breast tumors and significantly correlated with clinical progression. PDE3A induced the inflammatory nuclear factor NFκB signaling pathway by suppressing cAMP/PKA, which promotes the expression of the stem cell marker OCT4. In addition, PDE3A also promoted the translocation of CCDC88A from the cytoplasm to nuclei, thereby boosting the invasion–metastasis cascade in breast cancer. Most importantly, the PDE3A-selective inhibitor cilostazol dramatically suppressed breast tumor growth and reduced metastasis to the lungs in xenograft breast cancer models, with minimum toxicity. Taken together, we show that PDE3A could predispose patients with breast cancer to metastases by acting as a mediator of cancer stemness. PDE3A is a potential therapeutic target for advanced breast cancer.
Site-Specific PEGylation of Anti-Mesothelin Recombinant Immunotoxins Increases Half-life and Antitumor Activity
Authors: Zheng Zeliang , Okada Ryuhei , Kobayashi Hisataka , Nagaya Tadanobu , Wei Junxia , Zhou Qi , Lee Fred , Bera Tapan K. , Gao Yun , Kuhlman William , Tai Chin-Hsien , Pastan Ira 
Published: December 2019

Abstract
Recombinant immunotoxins (RIT) are chimeric proteins containing an Fv that binds to tumor cells, fused to a fragment of Pseudomonas exotoxin (PE) that kills the cell. Their efficacy is limited by their short half-life in the circulation. Chemical modification with polyethylene glycol (PEG) is a well-established method to extend the half-lives of biologics. Our goal was to engineer RITs with an increase in half-life and high cytotoxic activity. We introduced single cysteines at different locations in five anti-mesothelin RITs and employed site-specific PEGylation to conjugate them to 20-kDa PEG. Because our previous PEGylation method using β-mercaptoethanol reduction gave poor yields of PEG-modified protein, we employed a new method using tris(2-carboxyethyl)phosphine to reduce the protein and could PEGylate RITs at approximately 90% efficiency. The new proteins retained 19% to 65% of cytotoxic activity. Although all proteins are modified with the same PEG, the radius of hydration varies from 5.2 to 7.1, showing PEG location has a large effect on protein shape. The RIT with the smallest radius of hydration has the highest cytotoxic activity. The PEGylated RITs have a 10- to 30-fold increase in half-life that is related to the increase in hydrodynamic size. Biodistribution experiments indicate that the long half-life is due to delayed uptake by the kidney. Antitumor experiments show that several PEG-RITs are much more active than unmodified RIT, and the PEG location greatly affects antitumor activity. We conclude that PEGylation is a useful approach to improve the half-life and antitumor activity of RITs.
Use of Biomarker Modulation in Normal Mammary Epithelium as a Correlate for Efficacy of Chemopreventive Agents Against Chemically Induced Cancers
Authors: Lubet Ronald A. , Heckman-Stoddard Brandy M. , Fox Jennifer T. , Moeinpour Fariba , Juliana M. Margaret , Shoemaker Robert H. , Grubbs Clinton J. 
Published: December 2019

AbstractIn both estrogen receptor/progesterone receptor–positive (ER+/PR+) human breast cancer and in ER+/PR+ cancers in the methylnitrosourea (MNU)-induced rat model, short-term modulation of proliferation in early cancers predicts preventive/therapeutic efficacy. We determined the effects of known effective/ineffective chemopreventive agents on proliferative index (PI) in both rat mammary epithelium and small cancers. Female Sprague-Dawley rats were treated with MNU at 50 days of age. Five days later, the rats were treated with the individual compounds for a period of 14 days. At that time, normal mammary tissue from the inguinal gland area was surgically removed. After removal, the rats remained on the agents for an additional 5 months. This cancer prevention study confirmed our prior results of striking efficacy with tamoxifen, vorozole, Targretin, and gefitinib, and no efficacy with metformin, naproxen, and Lipitor. Employing a separate group of rats, the effects of short-term (7 days) drug exposure on small palpable cancers were examined. The PI in both small mammary cancers and in normal epithelium from control rats was &gt;12%. In agreement with the cancer multiplicity data, tamoxifen, vorozole, gefitinib, and Targretin all strongly inhibited proliferation (&gt;65%; P &lt; 0.025) in the normal mammary epithelium. The ineffective agents metformin, naproxen, and Lipitor minimally affected PI. In the small cancers, tamoxifen, vorozole, and Targretin all reduced the PI, while metformin and Lipitor failed to do so. Thus, short-term changes in the PI in either normal mammary epithelium or small cancers correlated with long-term preventive efficacy in the MNU-induced rat model.
Immunoregulation and Clinical Implications of ANGPT2/TIE2+ M-MDSC Signature in Non–Small Cell Lung Cancer
Authors: Lauret Marie Joseph Elodie , Laheurte Caroline , Jary Marine , Boullerot Laura , Asgarov Kamal , Gravelin Eléonore , Bouard Adeline , Rangan Laurie , Dosset Magalie , Borg Christophe , Adotévi Olivier 
Published: December 2019

Abstract
Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non–small cell lung cancer (NSCLC). Greater numbers of circulating TIE2+ M-MDSCs were detected in patients with NSCLC compared with healthy subjects, and this accumulation correlated with ANGPT2 concentration in blood. The presence of an ANGPT2-rich environment was associated with impairment of preexisting T-cell responses against tumor-associated antigens (TAA) in patients with NSCLC. We demonstrated that ANGPT2 sensitizes TIE2+ M-MDSCs such that these cells suppress TAA-specific T cells. In patients with NSCLC, upregulation of the ANGPT2/TIE2+ M-MDSC signature in blood was associated with a poor prognosis. Our results identify the ANGPT2/TIE2+ M-MDSC axis as a participant in tumor immune evasion that should be taken into account in future cancer immunotherapy.
CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy
Authors: Kagamu Hiroshi , Kitano Shigehisa , Yamaguchi Ou , Yoshimura Kenichi , Horimoto Katsuhisa , Kitazawa Masashi , Fukui Kazuhiko , Shiono Ayako , Mouri Atsuhito , Nishihara Fuyumi , Miura Yu , Hashimoto Kosuke , Murayama Yoshitake , Kaira Kyoichi , Kobayashi Kunihiko 
Published: December 2019

AbstractAccumulating evidence indicates that CD8+ T cells in the tumor microenvironment and systemic CD4+ T-cell immunity play an important role in mediating durable antitumor responses. We longitudinally examined T-cell immunity in the peripheral blood of patients with non–small lung cancer and found that responders had significantly (P &lt; 0.0001) higher percentages of effector, CD62Llow CD4+ T cells prior to PD-1 blockade. Conversely, the percentage of CD25+FOXP3+ CD4+ T cells was significantly (P = 0.034) higher in nonresponders. We developed a formula, which demonstrated 85.7% sensitivity and 100% specificity, based on the percentages of CD62Llow CD4+ T cells and CD25+FOXP3+ cells to predict nonresponders. Mass cytometry analysis revealed that the CD62Llow CD4+ T-cell subset expressed T-bet+, CD27−, FOXP3−, and CXCR3+, indicative of a Th1 subpopulation. CD62Llow CD4+ T cells significantly correlated with effector CD8+ T cells (P = 0.0091) and with PD-1 expression on effector CD8+ T cells (P = 0.0015). Gene expression analysis revealed that CCL19, CLEC-2A, IFNA, IL7, TGFBR3, CXCR3, and HDAC9 were preferentially expressed in CD62Llow CD4+ T cells derived from responders. Notably, long-term responders, who had &gt;500-day progression-free survival, showed significantly higher numbers of CD62Llow CD4+ T cells prior to PD-1 blockade therapy. Decreased CD62Llow CD4+ T-cell percentages after therapy resulted in acquired resistance, with long-term survivors maintaining high CD62Llow CD4+ T-cell percentages. These results pave the way for new treatment strategies for patients by monitoring CD4+ T-cell immune statuses in their peripheral blood.
Review of Scaura Schwarz, 1938 (Hymenoptera: Apidae: Meliponini)
Authors: NOGUEIRA DAVID SILVA , DOS SANTOS JÚNIOR JOSÉ EUSTÁQUIO , DE OLIVEIRA FAVÍZIA FREITAS , DE OLIVEIRA MARCIO LUIZ 
Published: December 2019

Scaura Schwarz is a small, widely distributed Neotropical genus of stingless bees whose workers and males have the metabasitarsus as broad as or wider than the metatibia. The genus currently includes four valid species. A species complex composed of three additional species are described here as new (S. amazonica sp. n., S. aspera sp. n. and S. cearensis sp. n.). In addition to the descriptions and redescriptions of the species of Scaura, an illustrated identification key is presented, as well as updated geographical records.
From icon to punk portrait: The iconicity of the ruler image in the context of the transformation of the idea of the Serbian state
Authors: Bogusławska Magdalena 
Published: December 2019

From icon to punk portrait: The iconicity of the ruler image in the context of the transformation of the idea of the Serbian stateThe article describes transformation in the iconographic forms of power representations in Serbian culture as determinants of the evolution of the idea of the State and Serbian political culture. In visual terms, the key stages of their development correspond to the genealogical dynastic image of the religious character (loza) in the middle ages, and the “disenchanted” historical and representative portrait of a ruler that was subordinated to the national idea on the threshold of modernity. These forms not only participate in the establishment of political leadership and the creation of the field of power, but they also stimulate their change. The author examines these issues from the perspective of visual studies, which problematize the phenomenon of the performativity of the image. A particular variation of the performativity of the image is iconicity, understood as drafting and making present reality using esthetic and visual values. The aim of the analysis is to show how the local, namely Serbian, pattern of culture of power models the universal mechanisms of forming and legitimizing the authority of the State. Od ikony do punk portretu. Ikoniczność wizerunku władcy w kontekście przemian idei państwa serbskiegoArtykuł dotyczy przeobrażeń ikonograficznych form reprezentacji władzy w kulturze serbskiej jako wyznaczników ewolucji idei państwa oraz kultury politycznej Serbów. W wymiarze wizualnym kluczowym etapom ich rozwoju odpowiadają: w średniowieczu genealogiczny wizerunek dynastyczny o charakterze religijnym (loza), a u progu nowożytności „odczarowany” portret historyczny i reprezentacyjny władcy, podporządkowany idei narodowej. Formy te uczestniczą w stanowieniu przywództwa politycznego i wytwarzaniu pola władzy oraz stymulują ich zmianę. Autorka rozpatruje te zagadnienia z perspektywy visual studies, które problematyzują zjawisko performatywności obrazu. Jej szczególną odmianą jest ikoniczność, rozumiana jako stanowienie i uobecnianie rzeczywistości za pomocą wartości estetycznych, wizualnych. Celem analizy jest ukazanie, w jaki sposób lokalny, tj. serbski wzór kultury władzy modeluje uniwersalne mechanizmy formowania i legitymizacji autorytetu państwa.
Rupture – Integration – Renewal: The gathering in Dalma and the creation of a political community in the Chronicle of the Priest of Dioclea
Authors: Kowalski Wawrzyniec 
Published: December 2019

Rupture – Integration – Renewal: The gathering in Dalma and the creation of a political community in the Chronicle of the Priest of DiocleaIn this paper I would like to discuss an excerpt from the Chronicle of the Priest of Dioclea that concerns a great gathering ordered by the newly baptized King Svetopelek at the fields of Dalma. The Chronicle is a rather mysterious and controversial source which presents the history of a fictional state stretching through medieval Dalmatia and the hinterland. The division of the state which took place during Svetopelek’s reign shows how the chronicler believed the kingdom was to be governed. Space played a special role in the narrative about the gathering. Describing the King’s actions, the Priest of Dioclea simultaneously offered a geographical and political vision of a new order. The interpretation of the events that took place in Dalma (the coronation ceremony, the process of defining the borders of the kingdom and, above all, the unification of the newly founded state community) led to the conclusion that the chronicler was most interested in the problem of creating a political community of two previously hostile groups: the barbarian Slavs and the inhabitants of coastal cities, who were the heirs of the ancient world. Zerwanie, scalenie, odnowa. Wiec w Dalmie i tworzenie się wspólnoty politycznej w Latopisie popa DukljaninaLatopis popa Dukljanina to tajemnicza i kontrowersyjna narracja, która przedstawia losy fikcyjnego państwa rozciągającego się na terenie średniowiecznej Dalmacji i interioru. W artykule omówiono jego fragment poświęcony wydarzeniom na polach Dalmy, gdzie według dziejopisu odbył się wielki zjazd zwołany przez króla Svetopelka. Przedstawiono tu liczne opinie i pomysły dotyczące interpretacji opisanych wydarzeń: ceremonię koronacyjną, proces wytyczania granic, a przede wszystkim jednanie wspólnoty nowego państwa, i sformułowano wniosek, że Dukljanina najbardziej interesowała kwestia wyodrębniania się społeczności politycznej dwóch grup – dzikich Słowian i będących spadkobiercami antycznego świata mieszkańców wybrzeża.
Dynamics of the particular and the common: Monuments and patriotic tourism in socialist Yugoslavia – a case study of Kosovo
Authors: Rogoś Agata 
Published: December 2019

Dynamics of the particular and the common: Monuments and patriotic tourism in socialist Yugoslavia – a case study of KosovoThis paper reflects on two case studies of monuments in Socialist Yugoslavia in Kosovo, commemorating World War II partisans in Mitrovica (1973) and Landovica (1963) and their performative functions as a part of the phenomena of patriotic tourism. Both examples refer to inter-ethnic (Serbian and Albanian) relations bound by the slogan brotherhood and unity. Boro and Ramiz, two figures present in Yugoslav collective memory and represented through monuments and orality, have become a symbol of unity in Socialist Yugoslavia. War memorials and monuments have been raised all over the territory of socialist Yugoslavia and created an invisible network of remembrance and identity. The most important sites, as those analyzed in this paper, have become destinations of patriotic tourism: they were visited by millions every year and were associated with huge print runs of tourist propaganda production such as maps, guide-books and postcards (apart from commercial tourist attractions, almost every postcard produced in socialist Yugoslavia presented a nearby monument or memorial). Dynamika indywidualizmu i wspólnoty. Pomniki i turystyka patriotyczna w socjalistycznej Jugoslawii – przypadek KosowaNiniejszy artykuł prezentuje dwa studia przypadku dotyczące pomników socjalistycznej Jugosławii na terenie Kosowa, upamiętniających partyzantów z czasów II wojny światowej w Mitrowicy (1973) i Landovicy (1963) oraz ich funkcji performatywnych w ramach zjawiska turystyki patriotycznej. Oba przykłady odnoszą się do relacji międzyetnicznych (serbskich i albańskich) połączonych hasłem: braterstwo i jedność. Dwaj partyzanci obecni w zbiorowej pamięci dzięki pomnikom i historii mówionej – Boro i Ramiz – stali się symbolem jedności w socjalistycznej Jugosławii. Pomniki i miejsca pamięci upamiętniające walkę usłały całe terytorium socjalistycznej Jugosławii i stworzyły niewidzialną sieć pamięci i tożsamości. Najważniejsze miejsca, jak te analizowane w artykule, stały się celami turystyki patriotycznej i są odwiedzane przez miliony turystów każdego roku. Były one związane z prowadzoną na dużą skalę propagandą turystyczną: publikowanymi w dużych nakładach mapami, przewodnikami i pocztówkami, które oprócz komercyjnych atrakcji turystycznych prezentowały pobliskie miejsca pamięci i pomniki.
Kościół ewangelicki augsburskiego wyznania na Śląsku Cieszyńskim na przełomie XIX i XX wieku a poszukiwanie tożsamości językowo-narodowej
Authors: Kubok Beata 
Published: December 2019

The Evangelical Church of the Augsburg Confession in Cieszyn Silesia at the turn of the 20th century and searching for language and national identityThe article analyses the constituent parts of the identity of the Evangelical Church Augsburg Confessions (Lutheran) in Cieszyn Silesia from the 2nd half of the 19th century to 1945 years. The statutory time frames have allowed to trace the correlates of national culture, which is sourced in 19th century national movements. They led to the construction of a retrospective national history, in which in first place was a unique position of the Polish language and the confessional identity was defined in terms of Polishness. This predetermined national-religious pattern set for a period of about 100 years the nature of the Lutheran Church in Cieszyn Silesia. The article, in addition to the theoretical part, was supplemented with a study of the author's own archival documents of the seven Zaolzian Protestant congregations. Kościół ewangelicki augsburskiego wyznania na Śląsku Cieszyńskim na przełomie XIX i XX wieku a poszukiwanie tożsamości językowo-narodowejW artykule przeanalizowane zostały części składowe tożsamości Kościoła ewangelickiego augsburskiego wyznania (luterańskiego) na Śląsku Cieszyńskim od drugiej połowy XIX wieku do 1945 roku. Tak stanowione ramy czasowe pozwoliły prześledzić korelaty kultury narodowej, mające swe źródło w XIX-wiecznych ruchach narodowych. Doprowadziły one do konstruowania retrospektywnej historii narodowej, w której pierwsze miejsce zajmowała wyjątkowa pozycja języka polskiego, a tożsamość konfesyjna została zdefiniowana w kategoriach „polskości”. Ten z góry przyjęty wzorzec narodowo-religijny wyznaczył na okres około 100 lat charakter Kościoła luterańskiego na Śląsku Cieszyńskim. Artykuł, oprócz części teoretycznej, został uzupełniony o badania własne autorki archiwalnych dokumentów siedmiu zaolziańskich zborów protestanckich.
Anthony D. Smith (1939-2016) jako socjolog narodu: szkic do portretu intelektualnego
Authors: Poniedzialek Jacek 
Published: December 2019

Anthony D. Smith (1939-2016) as a sociologist of the nation: a sketch to an intellectual portraitThe aim of this article is to present a sketch of the intellectual biography of Anthony D. Smith who is the creator of the theoretical perspective in sociology of nation, called ethnosymbolism. The text analyzes the impact of his childhood and early school education in a later life as a scholar and his future research of nations. It also presents the stages of his education and the interest in national issues shaped at that time, in particular studies on ancient history, general historiography or classic sociological theories. The article shows three stages of the formation of Smith's scientific views, from consistent modernism, to its correction, to radical ethnosymbolism. The text is a sketch of an intellectual biography, not a detailed analysis of the ethnosymbolic approach itself. Anthony D. Smith (1939-2016) jako socjolog narodu: szkic do portretu intelektualnegoCelem artykułu jest zaprezentowanie szkicu biografii intelektualnej Anthony’ego D. Smitha, twórcy perspektywy teoretycznej w socjologii narodu nazywanej etnosymbolizmem. W tekście dokonana zostanie analiza wpływu dzieciństwa i wczesnej edukacji szkolnej uczonego na podejmowane przez niego w przyszłości badania narodów. Ukazane zostaną etapy jego edukacji i kształtujące się wówczas zainteresowania problematyką narodową, w szczególności studia nad historią starożytną, historiografią powszechną czy klasycznymi teoriami socjologicznymi. Wyodrębnione zostały trzy etapy formowania się poglądów naukowych Smitha, od konsekwentnego modernizmu, przez jego korektę, do radykalnego etnosymbolizmu. Tekst jest szkicem biografii intelektualnej, a nie szczegółową analizą samego podejścia etnosymbolicznego.