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Myeloid Cell-based Immunotherapies for the Treatment of Cancer
No full textA key question in cancer immunotherapy is which features dictate therapeutic response versus non-response. Therapeutic responses to checkpoint blockade immunotherapies still hover around 15-20% across most cancers. Critical barriers to therapeutic response include the immune suppressive tumor microenvironment (TME), which is predominated by tumor-associated macrophages (TAMs). These TAMs generally promote tumor growth, invasion, metastasis, and resistance to treatment. Due to their high plasticity, TAMs can exhibit various phenotypes. Recent studies have revealed that some TAMs actually stimulate the immune response, challenging their traditional view as purely immunosuppressive. While prior approaches have been made to therapeutically target TAMs using antibodies binding cell surface proteins or growth factor pathways, these approaches have had limited clinical success. A possible reason why these approaches failed is that they targeted macrophages without identifying an immunological direction. Here, we show that systematic identification of stimuli to induce interleukin-12 (IL-12), a strongly anti-tumor cytokine produced by macrophages, provides novel combination therapies to induce IL-12 production natively within TAMs. We combine a high-throughput molecular screen for IL-12-inducing compounds with a cyclodextrin-based nanoparticle to create a Highly Active Myeloid Therapy (HAMT) that can complex small molecule immune modulatory drugs for simultaneous delivery into macrophages. By employing this simultaneous delivery strategy, we overcome the challenges of the uneven drug distribution that often results from differing pharmacokinetics in separate administrations to modulate macrophage more effectively.
We hypothesized that a novel TAM-targeted nanoparticle, encapsulated with triple small-molecule drugs targeting the Janus Tyrosine Kinase (JAK1/2), the non-canonical nuclear factor kappa light chain enhancer of activated B cells (NF-κB), and toll-like receptor (TLR) pathways, would trigger native macrophage production of IL-12 to mitigate the immune suppressive microenvironment within tumors. To test the mechanism further, we applied intravital microscopy and flow cytometry to confirm that most nanoparticle uptake was into TAMs but not tumor cells or lymphocytes. We also demonstrate that HAMT treatment cohorts showed fewer terminally exhausted T cells compared to the control groups. Finally, we performed RNA sequencing on HAMT-stimulated bone marrow-derived macrophages, which characterized a novel TAM phenotype by an over-expression of IL-12, MARCO, DC-SIGN, and SIGNR7 and the absence of ISG, which includes the inhibitory factors PDL1 and IDO1/2
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
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Elevated ALDH Expression Impairs Dendritic Cell Function and Contributes to Immunotherapy Resistance in Bladder Cancer
Get PDFImmunotherapy has significantly improved cancer treatment, but a significant proportion of patients do not respond to therapy. This study investigates the role of aldehyde dehydrogenase 1A1 (Aldh1A1) and its metabolite retinoic acid (RA) in shaping the tumor microenvironment and influencing immunotherapy response in bladder cancer. Analysis of two murine bladder cancer cell lines, BBNF2 and BBNF9, revealed that BBNF9 tumors, which are resistant to anti-PD-1 therapy, express higher levels of Aldh1A1 compared to immunotherapy responsive BBNF2 tumors. In vitro studies demonstrated that RA impairs dendritic cell maturation, IL-12 production, and capacity to stimulate T cells, a process mediated by the retinoic acid receptor RXRα. To further elucidate the role of Aldh1A1 in immunotherapy resistance, Aldh1A1 was knocked out in BBNF9 cells using CRISPR-Cas9. Aldh1A1-deficient BBNF9 tumors exhibited increased dendritic cell infiltration, enhanced trafficking of cross-presenting cDC1s to tumor-draining lymph nodes, and reduced recruitment of immunosuppressive neutrophil subsets. Importantly, Aldh1A1 knockout sensitized BBNF9 tumors to anti-PD-1 therapy, characterized by increased T cell infiltration and exhaustion phenotypes. These findings provide mechanistic insights into how the Aldh1a1-RA axis modulates dendritic cell function and contributes to immunotherapy resistance in bladder cancer.Graduate Educatio
Variations on the Author
Get PDF“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
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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