1,724,630 research outputs found
[Veto of H. 4187, R. 323]
No full textThis veto message from Governor Mark Sanford vetoes H. 4187, R. 323, which deletes the 25-year maximum time period for leases between local airports and private parties
Safety of fuses after the ratification of STANAG 4187
No full textW artykule znajdują się wymagania dotyczące projektowania i eksploatacji zapalników w zakresie bezpieczeństwa zawarte w STANAG 4187 oraz AOP 16.Some specifications for the design and use of fuses regarding the recommendations of safety included in STANAG 4187 and AOP 16 are presented in the paper
Linked collectors and determiners for: Checklist of Serengeti Ecosystem Grasses.
No full textNatural history specimen data linked to collectors and determiners held within, "Checklist of Serengeti Ecosystem Grasses". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/e396bc9e-99f8-4187-85c5-ef2b4e500392">https://bionomia.net/dataset/e396bc9e-99f8-4187-85c5-ef2b4e500392</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/e396bc9e-99f8-4187-85c5-ef2b4e500392">https://gbif.org/dataset/e396bc9e-99f8-4187-85c5-ef2b4e500392</a>. Formatted as a Frictionless Data package
Linked collectors and determiners for: Insect Occurrence Data from MIZA.
No full textNatural history specimen data linked to collectors and determiners held within, "Insect Occurrence Data from MIZA". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/ca0d1f8f-4ba5-4187-82ec-ed8a66745b67">https://bionomia.net/dataset/ca0d1f8f-4ba5-4187-82ec-ed8a66745b67</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/ca0d1f8f-4ba5-4187-82ec-ed8a66745b67">https://gbif.org/dataset/ca0d1f8f-4ba5-4187-82ec-ed8a66745b67</a>. Formatted as a Frictionless Data package
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Comentario de la Sentencia del Tribunal Supremo de 10 de noviembre de 2021 (4187 / 2021)
Full text linkComentario de la Sentencia del Tribunal Supremo 4187 / 2021, de 10 de noviembr
Kryptonabtrennung aus dem Aufloeserabgas einer Wiederaufarbeitungsanlage durch Tieftemperaturrektifikation Sammlung der Beitraege
No full textTIB: ZA 5141 (4187) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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Abstract 4187: Combined MEK and STAT3 inhibition reprograms the tumor microenvironment to overcome immunotherapy resistance in pancreatic cancer
No full textAbstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune exclusion, stromal desmoplasia, and resistance to immune checkpoint inhibition (ICI). We have previously demonstrated that reciprocally activated RAS/RAF/MEK/ERK and JAK/STAT3 pathways mediate therapeutic resistance, while combined MEK and STAT3 inhibition (MEKi+STAT3i) overcomes this resistance in preclinical PDAC models. Given the dramatic decrease in tumor burden observed following MEKi+STAT3i, we investigated its effect on the stromal and immune microenvironment.
Methods: Ptf1aCre/+KrasG12D/+Tgfbr2flox/flox (PKT) mice were treated with vehicle, trametinib (MEKi, 3.3 mg/Kg, oral gavage three times weekly), ruxolitinib (STAT3i, 20 mg/Kg, oral gavage three times weekly), αPD-1 antibody (200 µg/mouse, i.p. injection twice weekly), combined MEKi+STAT3i or MEKi+STAT3i with αPD-1 beginning at 4-4.5 weeks of age. Mice were sacrificed after four weeks of treatment and tumors were harvested for single cell RNA sequencing, and high-dimensional immune-profiling by mass cytometry and flow cytometry.
Results: Single-cell transcriptomic analysis revealed that combined MEKi+STAT3i not only altered stromal architecture but also reprogramed tumor-resident CAFs from Il6/Cxcl1-expressing inflammatory phenotype towards Ly6a/Cd34-expressing fibroblast phenotype with both mesenchymal and hematopoietic progenitor-like properties. This stromal plasticity was associated with a striking attenuation and reprogramming of F4/80+ macrophages, M2-like macrophages (F4/80+CD206+), and MDSCs (CD11b+F4/80-Ly6G+/Ly6C+), as well as enhanced trafficking of CD4+ and CD8+ T-cells which exhibited a distinct effector and anti-apoptotic transcriptional program. The addition of MEKi+STAT3i to PD-1 blockade overcomes immune checkpoint resistance by significantly augmenting anti-tumor responses and dramatically improving survival in PKT mice, compared with vehicle treatment (median 181 vs. 44 days, p<0.0001) or anti-PD-1 monotherapy (median 181 vs. 57 days, p=0.0005). The addition of MEKi+STAT3i to PD-1 blockade not only augmented the recruitment of activated and memory T-cell populations, but also improved their degranulating capacity and functional cytotoxicity compared to PD-1 blockade alone. Importantly, treatment of a patient with chemotherapy-refractory metastatic PDAC with MEKi (Trametinib), STAT3i (Ruxolitinib), and PD-1 inhibitor (Nivolumab) was well-tolerated and yielded significant clinical benefit.
Conclusion: These data uncover a novel paradigm in which combined MEKi+STAT3i reprograms stromal inflammation and immune tolerance to overcome immunotherapy resistance in PDAC. The clinical efficacy of combined MEKi+STAT3i and anti-PD1 treatment provides encouraging signals for its translatability and is currently being pursued in a clinical trial.
Citation Format: Vanessa Tonin Garrido, Jashodeep Datta, Xizi Dai, Anna Bianchi, Iago De Castro Silva, Purushottam Lamichhane, Siddharth Mehra, Samara P. Singh, Austin R. Dosch, Oliver Umland, Michael n N. VanSaun, Peter J. Hosein, Nagaraj Nagathihalli, Nipun Merchant. Combined MEK and STAT3 inhibition reprograms the tumor microenvironment to overcome immunotherapy resistance in pancreatic cancer [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 4187
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